Taurine compositions suitable for inhalation

ABSTRACT

The invention discloses spray-dried compositions for inhalation and methods for preparing such powder compositions. The compositions of the invention are produced by spray-drying taurine under conditions that (i) retain the physical and chemical stability of the composition during spray drying and upon storage, (ii) protect the powder composition from aggregation and (iii) provide particles suitable for aerosolisation.

The present invention relates to stable materials, compositionscomprising such materials suitable for inhalation and methods forpreparing such compositions.

BACKGROUND OF THE INVENTION

The process of spray drying has been widely used in the production ofpharmaceuticals since the 1940s (Corrigan, 1995). The food industry alsocommonly employs spray drying to produce food products demonstratingenhanced stability and suitable for long term storage (Sliwinski et al.,2004). Spray drying is a one step process used to convert a liquid basedfeedstock (such as a solution, suspension or emulsion) into a driedpowder form by atomizing the feedstock in droplets, into a hotdrying-medium, typically air or nitrogen. The process provides enhancedcontrol over particle size, size distribution, particle shape, density,purity and structure. As formulators are able to control theseparameters so precisely, spray drying as a possible method forformulating dry powder compositions intended for pulmonary delivery hasalso been investigated in recent years (WO 96/32194).

Spray drying active pharmaceutical ingredients (API) or biologicalmaterial suitable for inhalation normally requires the presence ofstabilizing excipients and/or diluents.

The de-facto spray drying excipient of choice is often Mannitol as itpossesses many advantageous properties. Mannitol will readily dry in acrystalline state, is water soluble and is considered non-hygroscopic asit picks up less than 1% moisture at relative humidity as high as 70%(Handbook of Pharmaceutical Excipients, 6^(th) Edition, R. C. Rowe). Inaddition it can pick up 10% of mass in water at humidity's >70% RH.However despite mannitol's attractive stabilizing capabilities, it is atussive agent and will induce coughing when administered via thepulmonary route.

As an alternative choice excipient, trehalose is often used for spraydrying compositions. Trehalose (α-D-glucopyranosyl-α-D-glucopyranoside)is a naturally occurring, non-reducing disaccharide which was initiallyfound to be associated with the prevention of desiccation damage incertain plants and animals which can dry out without damage and canrevive when rehydrated. Trehalose however does not spray dry completelycrystalline and will instead form an amorphous matrix. This amorphousmatrix is hygroscopic and will readily absorb water. Spray-driedtrehalose therefore suffers from physical stability issues, principallyparticle agglomeration, resulting in loss of primary particle size andaerosol performance characteristics.

Thus a need still exists for materials such as excipients for preparingstable inhalable compositions which exhibit excellent aerosolisationproperties and demonstrate very low levels of agglomeration. Ideally,such excipients will spray dry in a crystalline form and will possessvarious favourable attributes such as low toxicity (with no coughinduced side effects), low hygroscopicity, high melting point, with verylow moisture content (advantageous for long term storage).

SUMMARY OF THE INVENTION

The invention relates to a method for preparing conditioned taurine, themethod comprising a conditioning step, optionally a spray drying step,to produce taurine that:

(a) demonstrates no significant net change in the D₉₀ (±20%) after 7days of ambient storage; and(b) have a particle size (D₉₀) of <20 μm, but more preferably <10 μmafter 7 days of ambient storage,optionally and preferably in which a method zwitterionic neutralisationis facilitated during spray drying of the taurine.

The invention also relates to conditioned taurine, obtained orobtainable by the method of the invention and to a compositioncomprising conditioned taurine, such as a dry powder compositionsuitable for inhalation.

The invention further relates to a method for preparing conditionedtaurine the method comprising drying solubilised taurine, optionally byspray drying with one or more of the following parameters:

(a) the pH of the feedstock to be spray dried is acidic e.g. less thanpH 5, preferably equal to or less then pH 4, such as about pH 4;(b) wherein the feedstock concentration is between 0.1% and 10%, morepreferably between 1% and 5%;(c) the feedstock temperature is between 0.1° C. and 100° C., morepreferably between 20° C. and 70° C.;(d) the outlet temperature is between 50° C. and 120° C., morepreferably between 60° C. and 100° C.;(e) the T_((solid:gas)) ratio is between 2.000×10⁻⁶ and 2.750×10⁻³.

The invention also relates to a container comprising:

-   -   (a) conditioned taurine; or    -   (b) a composition comprising conditioned taurine.

The invention also relates to a method for preparing conditionedtaurine, the method being a multi-step process, in one embodiment atwo-step process, and in one further embodiment a one step process suchas spay drying.

FIGURES

FIG. 1 is a response plot of modelled residual results versus actualdata. The boxed area highlights the 8 conditioned taurine batches.

FIG. 2 is a variability chart showing how the 8 conditioned taurinebatches span the whole theoretical operating range for spray dryers. Theconditioned taurine batches are shown as a function of theT_((solid:gas)) ratios.

FIG. 3 is a plot showing the relationship of conditioned taurine batcheswhich obey a quadratic relationship with the D₉₀ of the PSD after 7 days(R²=0 0.91 Prob>F 0.0031).

FIG. 4 is a TGA (thermo-gravimetric analysis) graph depicting the weightloss mean as a percentage at the initial time point, T=0 for 24 samplesof spray-dried taurine.

FIG. 5 is a TGA (thermo-gravimetric analysis) graph depicting the weightloss mean as a percentage at the 7 day time point, T=7 days for 24samples of spray-dried taurine.

FIG. 6 is a DSC (differential scanning calorimetry) graph depicting asample of spray-dried taurine.

FIG. 7 depicts the pKa profile of taurine.

FIG. 8 depicts the pH profile and isoelectric point of taurine.

FIG. 9 lists the joint factor tests indicating significance of allvariables.

FIG. 10 is a graph depicting the PSD (particle size distribution) for aspray-dried trehalose/leucine/salbutamol powder composition obtained byspray-drying under Process A conditions where T=0.

FIG. 11 is a graph depicting the PSD (particle size distribution) for aspray-dried trehalose/leucine/salbutamol powder composition obtained byspray-drying under Process A, stored under ambient sealed conditionswhere T=24 hours.

FIG. 12 is a graph depicting the PSD (particle size distribution) for aspray-dried taurine/leucine/salbutamol powder composition obtained byspray-drying under Process B conditions where T=0.

FIG. 13 is a graph depicting the PSD (particle size distribution) for aspray-dried taurine/leucine/salbutamol powder composition obtained byspray-drying under Process B, stored under ambient sealed conditionswhere T=24 hours.

FIG. 14 is a graph depicting the PSD (particle size distribution) for aspray-dried trehalose/leucine/salbutamol powder composition obtained byspray-drying under Process B conditions where T=0.

FIG. 15 is a graph depicting the PSD (particle size distribution) for aspray-dried trehalose/leucine/salbutamol powder composition obtained byspray-drying under Process B, stored under ambient sealed conditionswhere T=24 hours.

FIG. 16 is a graph depicting the PSD (particle size distribution) for aspray-dried taurine/leucine/salbutamol powder composition obtained byspray-drying under Process B, stored open at 25° C./50% RH, where T=24hours.

DETAILED DESCRIPTION OF THE INVENTION

Taurine or 2-aminoethanesulfonic acid is an organic acid that isubiquitous in the human body, constituting 0.1% w/w of its total weight(EFSA Response Letter, EFSA-Q-2007-113, 2009). It has been shown to betolerable in excess of 1000 mg kg⁻¹ day⁻¹ by the EFSA with noindications of inhalation toxicity or intolerability. Taurine hasexceptionally low moisture sorption characteristics and is thusconsidered non-hygroscopic as it does not take up any water at arelative humidity of between 0% and 100%. It is also soluble in water,is not considered a tussive agent and when spray-dried, producesparticles with very low moisture content (less than 1% w/w, morepreferably less than 0.5% w/w).

Taurine is a versatile molecule with various important biologicalfunctions, including: antioxidation; conjugation of bile acids;modulation of calcium signalling; osmoregulation and membranestabilization. Taurine is also regularly used as a dietary supplementand as an ingredient in energy drinks.

Although there is little evidence in the literature of taurine beingutilised as an active pharmaceutical ingredient, it has been describedfor the treatment of cardiac failure, and a taurine based compositionhas been disclosed in the treatment of asthma and various otherrespiratory failures (WO 92/17170). In the latter example, the taurinebased composition was administered by pulmonary inhalation as anaerosolised solution.

Spray drying taurine to create inhalable taurine particles that do notagglomerate has proven surprisingly challenging.

In the present invention we have determined spray drying taurine undercertain conditions can result in particle agglomeration over 1 to 7 daysresulting in a loss of primary particles and negligible aerosolperformance.

However, under certain conditions taurine can be produced which issuitable for inhalation use, and does not display such agglomeration.Such taurine is referred to as conditioned taurine herein, and in oneaspect is made by the methods of the invention as disclosed herein,although other methods can be used. Conditioned taurine is suitablytaurine that demonstrates no significant net change in the D₉₀ (±20%)after 7 days of ambient storage and has a particle size (D₉₀) of <20 μm,but more preferably <10 μm after 7 days of ambient storage.

Provided herein is also a likely basis for the agglomeration of taurinewhich permits conditioned taurine to be produced by spray drying andother methods, the basis referred to herein as the zwitterionicneutralisation theory.

DEFINITIONS

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognise, or be able to ascertain using no morethan routine study, numerous equivalents to the specific proceduresdescribed herein. Such equivalents are considered to be within the scopeof this invention and are covered by the claims.

The term “Taurine” is intended to encompass salt forms or counterionformulations of taurine as well as isolated stereoisomers (e.g.D-Taurine or L-Taurine) and mixtures of stereoisomers. Derivatives andintermediates of taurine (e.g. hypotaurine) are also encompassed.

The term “Raw Taurine” refers to commercially available pure taurine.

The term “Processed Taurine” refers to taurine that has been spray-driedusing spray drying conditions with resulting taurine particles tendingto agglomerate (i.e. demonstrate a net change in the D₉₀ (>20%) after 7days of ambient storage) and have a particle size (D₉₀) of >20 μm after7 days of ambient storage.

The term “Conditioned Taurine” refers to taurine that has been preparedto obtain taurine particles that demonstrate very low levels ofagglomeration (i.e. demonstrate no significant net change in the D₉₀(±20%) after 7 days of ambient storage) and remain as aerosolisableprimary particles e.g. where particles have a particle size (D₉₀) of <20μm, but more preferably <10 μm after 7 days of ambient storage.

The term “Leucine” is intended to encompass salt forms or counterionformulations of leucine as well as isolated stereoisomers (e.g.D-Leucine or L-Leucine) and mixtures of stereoisomers. Derivatives andintermediates of leucine are also encompassed.

The term “Agglomerate” or “Agglomeration” refers to the process wherebyparticles cohere to one another to create particle clusters, whichdemonstrate larger particle dimensions.

The term “Aerosolised” or “Aerosolisable” refers to particles, whichwhen dispensed from a dry powder inhalation device, will remainsuspended in the inhaler's gas stream for an amount of time suitable forat least a portion of the particles to be inhaled by the patient,thereby reaching the patients lungs.

The term “Process Parameters” refers specifically to spray dryingparameters such as: drying gas flow rate; atomisation gas flow rate;feedstock pumping rate; outlet temperature; feedstock temperature;feedstock concentration and feedstock pH and buffer/acid type.

The term “D₁₀” refers to the size in microns below which 10% of theparticles reside on a volume basis.

The term “D₅₀” refers to the size in microns above or below which 50% ofthe particles reside on a volume basis.

The term “D₉₀” refers to the size in microns below which 90% of theparticles reside on a volume basis.

The term “Inhalation” or “Inhalable” refers to particles that aresuitable for pulmonary administration. Such particles typically have amean aerodynamic particle size of less than 10 μm, more preferably lessthan 5 μm and most preferably less than 3.5 μm.

The term “Process A” refers to a preferred spray drying process forproducing optimal trehalose particles suitable for inhalation using inone embodiment the Niro spray dryer.

The term “Process B” refers to a preferred spray drying process forproducing optimal taurine particles, namely conditioned taurineparticles suitable for inhalation using in one embodiment the Niro spraydryer.

The term “Ambient Conditions” refers to material sealed and stored atroom temperature at about 20° C.±2.0° C. in the laboratory.

The term “Medicament” refers to pharmaceutical active agents orbioactive material. Medicament may also refer to combinations ofpharmaceutical agents, combinations of bioactive material orcombinations of pharmaceutical agent and bioactive material.

The term “Container” refers to either a bulk storage container, such asa multi-dose reservoir for a dry powder inhaler, or unit dose containerssuch as a capsule or a blister. The capsule may be formed from variousmaterials e.g. gelatine, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC), starch, starchderivatives, chitosan or synthetic plastics, while the blister may beprovided in the form of a blister pack or blister strip.

The term “Passive Device” refers to a dry powder inhaler device in whicha patient's breathe is the only source of gas which provides the motiveforce in the device.

The term “Active Device” refers to a dry powder inhaler device in whicha source of compressed gas or an alternative energy source is used toprovide the motive force in the device.

The term “Glass Transition Temperature”, which is represented by thesymbol T_(g), refers to the temperature at which a composition changesfrom a glassy or vitreous state to a syrup or rubbery state. T_(g) isgenerally determined using differential scanning calorimetry (DSC).

The term “T_((solid:gas)) ratio” refers to the mass of taurine pervolume of drying gas per unit time in the spray dryer.

General Statements

As used in this specification and the claim(s), the use of the word “a”or “an” when used in conjunction with the term “comprising” in theclaim(s) and/or the specification may mean “one”, but it is alsoconsistent with the meaning of “one or more”, “at least one”, and “oneor more than one”. The use of the term “or” in the claim(s) is used tomean “and/or” unless explicitly indicated to refer to alternatives onlyor the alternatives are mutually exclusive, although the disclosuresupports a definition that refers to only alternatives and “and/or”.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “any combinations thereof” as used herein refers to allpermutations and mixtures of the listed items preceding the term. Forexample, “A, B, C, or any combinations thereof is intended to include atleast one of: A, B, C, AB, AC, BC, or ABC, and if order is important ina particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are mixtures thatcontain repeats of one or more items or terms, such as BB, AAA, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there 525 is no limit on the number of itemsor terms in any mixture, unless otherwise apparent from the context.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

Detailed Description Process

The invention relates to, inter alia, a method for preparing taurine,the method comprising a conditioning step, wherein taurine is producedin the form of particles that:

(a) demonstrate no significant net change in the D₉₀ (±20%) after 7 daysof ambient storage; and(b) have a particle size (D₉₀) of <20 μm, but more preferably <10 μmafter 7 days of ambient storage,optionally and preferably in which a method zwitterionic neutralisationis facilitated during drying of the taurine.

As taurine is a zwitterionic compound, it is believed that thesulphur-hydyl group of the taurine becomes ionised (oxidation) with theproton being added to the amine group (reduction), in the feedstock of aspray drying approach, and retains a charge even after drying. Thisleads to the material relaxing on storage which is believed to be thecharged groups neutralising resulting in a conformatorial structuralchange. This conformatorial change causes agglomeration of the particlesin the dry state, leading to a significant reduction in the aerosolperformance. It is believed the neutralisation has a vitrificationintermediate phase, which is the cause of the agglomeration.

In one aspect facilitation of zwitterionic neutralisation is theprevention or minimising of ionic interaction between the sulphur-hydylgroup of the taurine and the amine group, such as the use of conditionsthat minimise or prevent reduction of the amine group and/or oxidationof the sulphur-hydyl group.

Further, we have demonstrated in the examples herein that predictivemodels can be generated that allow modulation of the spray dryingparameters consistent with this theory to allow conditioned taurine asdefined herein to be produced.

Parameters that affect the zwitterionic neutralisation process include:

-   -   Drying Gas flow rate    -   Atomisation gas flow rate    -   Feedstock pumping rate    -   Outlet temperature    -   Feedstock temperature    -   Feedstock concentration    -   Feedstock pH and buffer/acid type

Thus in one aspect of the invention any one or more of the aboveparameters may be varied to allow conditioned taurine to be produced,and the invention relates to a method for spray drying taurine, whereinone or more or all of these properties are controlled to produceconditioned taurine, optionally wherein a model using one or more or allparameters is used to predict appropriate parameters for the productionof conditioned taurine.

In one embodiment of the invention the taurine is spray dried.

In one embodiment of the invention the pH of the feedstock to be spraydried is acidic e.g. less than pH 5 in one embodiment equal to or lessthen pH 4, such as about pH 4.

In a further aspect of the invention the feedstock concentration isbetween 0.1% and 10%, in one embodiment between 1% and 5%.

In another aspect of the invention the feedstock temperature is between0.1° C. and 100° C., in one embodiment between 20° C. and 70° C.

In still a further aspect of the invention the outlet temperature isbetween 50° C. and 120° C., in one embodiment between 60° C. and 100° C.

In another aspect of the invention the T_((solid:gas)) ratio is between2.000×10⁻⁶ and 2.750×10⁻³.

The production of conditioned taurine can be confirmed by:

(a) no significant net change in the D₉₀ (±20%) after 7 days of ambientstorage; and(b) a particle size (D₉₀) of <20 μm, but more preferably <10 μm after 7days of ambient storage following the drying process.

In a further aspect of the invention raw commercially available taurinemay be comminuted to reduce particle size before any processing toproduce conditioned taurine as described herein. Particle size reductionis preferably to form a particle of size less than 20 μm in diameter, inone embodiment less than 10 μm in diameter.

Comminution can be achieved through various processes in isolation, forexample media milling or jet milling (micronisation).

Conditioning is the process of allowing charge neutralisation induced,for example following the communition step.

For the avoidance of doubt the conditioning of taurine may be carriedout by spray drying but other techniques may also be used to produceconditioned taurine, such as fluid bed conditioning. Fluid bedconditioning is considered a one-step conditioning process but wouldadditionally require a separate comminution step and so a preferredmethod to achieve both the conditioned step and the comminution stepsimultaneously, repeatably and more economically is to use spray drying.

The method of preparing conditioned taurine may therefore involve amulti-step process, or in one embodiment a two-step process or in onefurther embodiment a one-step process such as spray drying.

Spray drying solubilises the taurine raw material and produces smallerparticles through atomisation, which in this sense, due to the sizereduction, is considered as comminuted.

In a further aspect of the present invention, the conditioned taurine ismade by a spray drying method comprising: providing a feedstockcomprising raw taurine in an aqueous solution or suspension, and spraydrying the feedstock under conditions to create particles thatdemonstrate no significant net change in the D₉₀ (±20%) after 7 days ofambient storage; and have a particle size (D₉₀) of <20 μm, but morepreferably <10 μm after 7 days of ambient storage.

Product

The invention relates to conditioned taurine obtained or obtainableusing the method of the invention, and to compositions comprising suchtaurine per se.

For example, the invention relates to a composition comprisingconditioned taurine, such as a dry powder composition suitable forinhalation.

In one embodiment the conditioned taurine is substantially incrystalline form, with at least 95% of the taurine or more having acrystalline form

In one embodiment of the invention, the conditioned taurine is presentin an amount less than 99.9% by weight based on the dry weight of thecomposition e.g. less than 98.5%, less than 90%, less than 80%, lessthan 70%, less than 60%, less than 50%, less than 40%, less than 30%,less than 20%, less than 10%, less than 5%, less than 2.5% by weightbased on the dry weight of the composition.

In a further embodiment of the invention, taurine has a moisture contentof less than 2% by weight, optionally less than 1% by weight, optionallyless than 0.5% by weight of conditioned taurine.

Compositions and Other Elements

In another embodiment of the present invention, the conditioned taurineis both suitable for use as, and for use as an excipient, carrier ordiluent in a pharmaceutical composition.

The taurine of the invention may be prepared in combination with othercomponents, such as drugs or excipients, for example in a co-spray driedprocess.

In one embodiment the taurine may be dried, e.g. co-spray dried withleucine in an aqueous solution or suspension, wherein the aqueoussolution or suspension is spray dried under conditions to produce acomposition comprising conditioned taurine and leucine suitable forinhalation.

In one embodiment the spray-dried composition comprising leucine willcomprise leucine present in an amount less than 10% by weight based onthe dry weight of the composition e.g. less than 9%, less than 8%, lessthan 7%, less than 6%, less than 5%, in one embodiment less than 4%, inone embodiment less than 3%, in one embodiment less than 2% by weightbased on the dry weight of the composition.

In a further in one embodiment of the present invention, a compositioncomprising taurine may also comprise an additive material such as aso-called force control agent. A force control agent is an agent whichreduces the cohesion between fine particles within the powdercomposition. Suitable force control agents include amino acids, metalstearates such as magnesium stearate, phospholipids, lecithin, colloidalsilicon dioxide and sodium stearyl fumarate. In one embodiment the forcecontrol agent is magnesium stearate.

Amino acids which are suitable for use in the present invention includealanine, leucine, isoleucine, lysine, valine, methionine orphenylalanine. In one embodiment the amino acid is leucine. Theinclusion of these amino acids improves the aerosol performance of thecomposition.

In yet a further embodiment of the present invention, the amino acid, inone embodiment leucine, is present in an amount less than 10% by weightbased on the dry weight of the composition e.g. less than 9%, less than8%, less than 7%, less than 6%, less than 5%, in one embodiment lessthan 4%, in one embodiment less than 3%, in one embodiment less than 2%by weight based on the dry weight of the composition.

In still a further embodiment of the present invention, the amino acidis predominately present on the surface of the conditioned taurine.Without wishing to be bound by theory this may result from the aminoacid's hydrophobic and surface active properties.

Actives

In yet a further aspect of the present invention, the compositionfurther comprises a medicament or a combination of medicaments selectedfrom the following:

1) Adrenergic agonists such as, for example, amphetamine, apraclonidine,bitolterol, clonidine, colterol, dobutamine, dopamine, ephedrine,epinephrine, ethylnorepinephrine, fenoterol, formoterol, guanabenz,guanfacine, hydroxyamphetamine, isoetharine, isoproterenol, isotharine,mephenterine, metaraminol, methamphetamine, methoxamine, methpentermine,methyldopa, methylphenidate, metaproterenol, metaraminol, mitodrine,naphazoline, norepinephrine, oxymetazoline, pemoline, phenylephrine,phenylethylamine, phenylpropanolamine, pirbuterol, prenalterol,procaterol, propylhexedrine, pseudoephedrine, ritodrine, salbutamol,salmeterol, terbutaline, tetrahydrozoline, tramazoline, tyramine andxylometazoline.2) Adrenergic antagonists such as, for example, acebutolol, alfuzosin,atenolol, betaxolol, bisoprolol, bopindolol, bucindolol, bunazosin,butyrophenones, carteolol, carvedilol, celiprolol, chlorpromazine,doxazosin, ergot alkaloids, esmolol, haloperidol, indoramin, ketanserin,labetalol, levobunolol, medroxalol, metipranolol, metoprolol, nebivolol,nadolol, naftopidil, oxprenolol, penbutolol, phenothiazines,phenoxybenzamine, phentolamine, pindolol, prazosin, propafenone,propranolol, sotalol, tamsulosin, terazosin, timolol, tolazoline,trimazosin, urapidil and yohimbine.3) Adrenergic neurone blockers such as, for example, bethanidine,debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine, guanoclorand guanoxan.4) Drugs for treatment of addiction, such as, for example,buprenorphine.5) Drugs for treatment of alcoholism, such as, for example, disulfiram,naloxone and naltrexone.6) Drugs for Alzheimer's disease management, includingacetylcholinesterase inhibitors such as, for example, donepezil,galantamine, rivastigmine and tacrin.7) Anaesthetics such as, for example amethocaine, benzocaine,bupivacaine, hydrocortisone, ketamine, lignocaine, methylprednisolone,prilocaine, proxymetacaine, ropivacaine and tyrothricin.8) Angiotensin converting enzyme inhibitors such as, for example,captopril, cilazapril, enalapril, fosinopril, imidapril hydrochloride,lisinopril, moexipril hydrochloride, perindopril, quinapril, ramipriland trandolapril.9) Angiotensin receptor blockers, such as, for example, candesartan,cilexetil, eprosartan, irbesartan, losartan, medoxomil, olmesartan,telmisartan and valsartan.10) Antiarrhythmics such as, for example, adenosine, amidodarone,disopyramide, flecainide acetate, lidocaine hydrochloride, mexiletine,procainamide, propafenone and quinidine.11) Antibiotic and antibacterial agents (including the beta-lactams,fluoroquinolones, ketolides, macrolides, sulphonamides andtetracyclines) such as, for example, aclarubicin, amoxicillin,amphotericin, azithromycin, aztreonam chlorhexidine, clarithromycin,clindamycin, colistimethate, dactinomycin, dirithromycin, doripenem,erythromycin, fusafungine, gentamycin, metronidazole, mupirocin,natamycin, neomycin, nystatin, oleandomycin, pentamidine, pimaricin,probenecid, roxithromycin, sulphadiazine and triclosan.12) Anti-clotting agents such as, for example, abciximab, acenocoumarol,alteplase, aspirin, bemiparin, bivalirudin, certoparin, clopidogrel,dalteparin, danaparoid, dipyridamole, enoxaparin, epoprostenol,eptifibatide, fondaparin, heparin (including low molecular weightheparin), heparin calcium, lepirudin, phenindione, reteplase,streptokinase, tenecteplase, tinzaparin, tirofiban and warfarin.13) Anticonvulsants such as, for example, GABA analogs includingtiagabine and vigabatrin; barbiturates including pentobarbital;benzodiazepines including alprazolam, chlordiazepoxide, clobazam,clonazepam, diazepam, flurazepam, lorazepam, midazolam, oxazepam andzolazepam; hydantoins including phenytoin; phenyltriazines includinglamotrigine; and miscellaneous anticonvulsants including acetazolamide,carbamazepine, ethosuximide, fosphenytoin, gabapentin, levetiracetam,oxcarbazepine, piracetam, pregabalin, primidone, sodium valproate,topiramate, valproic acid and zonisamide.14) Antidepressants such as, for example, tricyclic and tetracyclicantidepressants including amineptine, amitriptyline (tricyclic andtetracyclic amitryptiline), amoxapine, butriptyline, cianopramine,clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine,dosulepin, dothiepin, doxepin, imipramine, iprindole, levoprotiline,lofepramine, maprotiline, melitracen, metapramine, mianserin,mirtazapine, nortryptiline, opipramol, propizepine, protriptyline,quinupramine, setiptiline, tianeptine and trimipramine; selectiveserotonin and noradrenaline reuptake inhibitors (SNRIs) includingclovoxamine, duloxetine, milnacipran and venlafaxine; selectiveserotonin reuptake inhibitors (SSRIs) including citalopram,escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine,milnacipran, nomifensine, oxaprotiline, paroxetine, sertraline,sibutramine, venlafaxine, viqualine and zimeldine; selectivenoradrenaline reuptake inhibitors (NARIS) including demexiptiline,desipramine, oxaprotiline and reboxetine; noradrenaline and selectiveserotonin reuptake inhibitors (NASSAs) including mirtazapine; monoamineoxidase inhibitors (MAOIs) including amiflamine, brofaromine,clorgyline, a-ethyltryptamine, etoperidone, iproclozide, iproniazid,isocarboxazid, mebanazine, medifoxamine, moclobemide, nialamide,pargyline, phenelzine, pheniprazine, pirlindole, procarbazine,rasagiline, safrazine, selegiline, toloxatone and tranylcypromine;muscarinic antagonists including benactyzine and dibenzepin; azaspironesincluding buspirone, gepirone, ipsapirone, tandospirone and tiaspirone;and other antidepressants including acetaphenazine, ademetionine,S-adenosylmethionine, adrafinil, amesergide, amineptine, amperozide,benactyzine, benmoxine, binedaline, bupropion, carbamazepine,caroxazone, cericlamine, cotinine, fezolamine, flupentixol, idazoxan,kitanserin, levoprotiline, lithium salts, maprotiline, medifoxamine,methylphenidate, metralindole, minaprine, nefazodone, nisoxetine,nomifensine, oxaflozane, oxitriptan, phenyhydrazine, rolipram,roxindole, sibutramine, teniloxazine, tianeptine, tofenaci'n, trazadone,tryptophan, viloxazine and zalospirone.15) Anticholinetgic agents such as, for example, atropine, benzatropine,biperiden, cyclopentolate, glycopyrrolate, hyoscine, ipratropiumbromide, orphenadine hydrochloride, oxitroprium bromide, oxybutinin,pirenzepine, procyclidine, propantheline, propiverine, telenzepine,tiotropium, trihexyphenidyl, tropicamide and trospium.16) Antidiabetic agents such as, for example, pioglitazone,rosiglitazone and troglitazone.17) Antidotes such as, for example, deferoxamine, edrophonium chloride,fiumazenil, nalmefene, naloxone, and naltrexone.18) Anti-emetics such as, for example, alizapride, azasetron,benzquinamide, bestahistine, bromopride, buclizine, chlorpromazine,cinnarizine, clebopride, cyclizine, dimenhydrinate, diphenhydramine,diphenidol, domperidone, dolasetron, dronabinol, droperidol,granisetron, hyoscine, lorazepam, metoclopramide, metopimazine,nabilone, ondansetron, palonosetron, perphenazine, prochlorperazine,promethazine, scopolamine, triethylperazine, trifluoperazine,triflupromazine, trimethobenzamide and tropisetron.19) Antihistamines such as, for example, acrivastine, astemizole,azatadine, azelastine, brompheniramine, carbinoxamine, cetirizine,chlorpheniramine, cinnarizine, clemastine, cyclizine, cyproheptadine,desloratadine, dexmedetomidine, diphenhydramine, doxylamine,fexofenadine, hydroxyzine, ketotifen, levocabastine, loratadine,mizolastine, promethazine, pyrilamine, terfenadine and trimeprazine.20) Anti-infective agents such as, for example, antivirals (includingnucleoside and non-nucleoside reverse transcriptase inhibitors andprotease inhibitors) including aciclovir, adefovir, amantadine,cidofovir, efavirenz, famiciclovir, foscarnet, ganciclovir, idoxuridine,indinavir, inosine pranobex, lamivudine, nelfinavir, nevirapine,oseltamivir, palivizumab, penciclovir, pleconaril, ribavirin,rimantadine, ritonavir, ruprintrivir, saquinavir, stavudine,valaciclovir, zalcitabine, zanamivir, zidovudine and interferons; AIDSadjunct agents including dapsone; aminoglycosides including tobramycin;antifungals including amphotericin, caspofungin, clotrimazole, econazolenitrate, fluconazole, itraconazole, ketoconazole, miconazole, nystatin,terbinafine and voriconazole; anti-malarial agents including quinine;antituberculosis agents including capreomycin, ciprofloxacin,ethambutol, meropenem, piperacillin, rifampicin and vancomycin;beta-lactams including cefazolin, cefmetazole, cefoperazone, cefoxitin,cephacetrile, cephalexin, cephaloglycin and cephaloridine;cephalosporins, including cephalosporin C and cephalothin; cephamycinssuch as cephamycin A, cephamycin, cephamycin C, cephapirin andcephradine; leprostatics such as clofazimine; penicillins includingamoxicillin, ampicillin, amylpenicillin, azidocillin, benzylpenicillin,carbenicillin, carfecillin, carindacillin, clometocillin, cloxacillin,cyclacillin, dicloxacillin, diphenicillin, heptylpenicillin, hetacillin,metampicillin, methicillin, nafcillin, 2-pentenylpenicillin, penicillinN, penicillin 0, penicillin S and penicillin V; quinolones includingciprofloxacin, clinafloxacin, difloxacin, grepafloxacin, norfloxacin,ofloxacine and temafloxacin; tetracyclines including doxycycline andoxytetracycline; miscellaneous anti-infectives including linezolide,trimethoprim and sulfamethoxazole.21) Anti-neoplastic agents such as, for example, droloxifene, tainoxifenand toremifene.22) Antiparkisonian drugs such as, for example, amantadine,andropinirole, apomorphine, baclofen, benserazide, biperiden,benztropine, bromocriptine, budipine, cabergoline, carbidopa, eliprodil,entacapone, eptastigmine, ergoline, galanthamine, lazabemide, levodopa,lisuride, mazindol, memantine, mofegiline, orphenadrine,trihexyphenidyl, pergolide, piribedil, pramipexole, procyclidine,propentofylline, rasagiline, remacemide, ropinerole, selegiline,spheramine, terguride and tolcapone.23) Antipsychotics such as, for example, acetophenazine, alizapride,amisulpride, amoxapine, amperozide, aripiprazole, benperidol,benzquinamide, bromperidol, buramate, butaclamol, butaperazine,carphenazine, carpipramine, chlorpromazine, chlorprothixene,clocapramine, clomacran, clopenthixol, clospirazine, clothiapine,clozapine, cyamemazine, droperidol, flupenthixol, fluphenazine,fluspirilene, haloperidol, loxapine, melperone, mesoridazine,metofenazate, molindrone, olanzapine, penfluridol, pericyazine,perphenazine, pimozide, pipamerone, piperacetazine, pipotiazine,prochlorperazine, promazine, quetiapine, remoxipride, risperidone,sertindole, spiperone, sulpiride, thioridazine, thiothixene,trifluperidol, triflupromazine, trifluoperazine, ziprasidone, zotepineand zuclopenthixol; phenothiazines including aliphatic compounds,piperidines and piperazines; thioxanthenes, butyrophenones andsubstituted benzamides.24) Antirheumatic agents such as, for example, diclofenac, heparinoid,hydroxychloroquine and methotrexate, leflunomide and teriflunomide.25) Anxiolytics such as, for example, adinazolam, alpidem, alprazolam,alseroxlon, amphenidone, azacyclonol, bromazepam, bromisovalum,buspirone, captodiamine, capuride, carbcloral, carbromal, chloralbetaine, chlordiazepoxide, clobenzepam, enciprazine, flesinoxan,flurazepam, hydroxyzine, ipsapiraone, lesopitron, loprazolam, lorazepam,loxapine, mecloqualone, medetomidine, methaqualone, methprylon,metomidate, midazolam, oxazepam, propanolol, tandospirone, trazadone,zolpidem and zopiclone.26) Appetite stimulants such as, for example, dronabinol.27) Appetite suppressants such as, for example, fenfluramine,phentermine and sibutramine; and anti-obesity treatments such as, forexample, pancreatic lipase inhibitors, serotonin and norepinephrinere-uptake inhibitors, and anti-anorectic agents.28) Benzodiazepines such as, for example, alprazolam, bromazepam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flunitrazepam, flurazepam, halazepam,ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam,nitrazepam, nordazepam, oxazepam, prazepam, quazepam, temazepam andtriazolam.29) Bisphosphonates such as, for example, alendronate sodium, sodiumclodronate, etidronate disodium, ibandronic acid, pamidronate disodium,isedronate sodium, tiludronic acid and zoledronic acid.30) Blood modifiers such as, for example, cilostazol and dipyridamol,and blood factors.31) Cardiovascular agents such as, for example, acebutalol, adenosine,amiloride, amiodarone, atenolol, benazepril, bisoprolol, bumetanide,candesartan, captopril, clonidine, diltiazem, disopyramide, dofetilide,doxazosin, enalapril, esmolol, ethacrynic acid, flecanide, furosemide,gemfibrozil, ibutilide, irbesartan, labetolol, losartan, lovastatin,metolazone, metoprolol, mexiletine, nadolol, nifedipine, pindolol,prazosin, procainamide, propafenone, propranolol, quinapril, quinidine,ramipril, sotalol, spironolactone, telmisartan, tocainide, torsemide,triamterene, valsartan and verapamil.32) Calcium channel blockers such as, for example, amlodipine, bepridil,diltiazem, felodipine, flunarizine, gallopamil, isradipine, lacidipine,lercanidipine, nicardipine, nifedipine, nimodipine and verapamil.33) Central nervous system stimulants such as, for example, amphetamine,brucine, caffeine, dexfenfluramine, dextroamphetamine, ephedrine,fenfluramine, mazindol, methyphenidate, modafmil, pernoline, phentermineand sibutramine.34) Cholesterol-lowering drugs such as, for example, acipimox,atorvastatin, ciprofibrate, colestipol, colestyramine, bezafibrate,ezetimibe, fenofibrate, fluvastatin, gemfibrozil, ispaghula, nictotinicacid, omega-3 triglycerides, pravastatin, rosuvastatin and simvastatin.35) Drugs for cystic fibrosis management such as, for example,Pseudomonas aeruginosa infection vaccines (eg Aerugen™), alpha1-antitripsin, amikacin, cefadroxil, denufosol, duramycin, glutathione,mannitol, and tobramycin.36) Diagnostic agents such as, for example, adenosine and aminohippuricacid.37) Dietary supplements such as, for example, melatonin and vitaminsincluding vitamin E.38) Diuretics such as, for example, amiloride, bendroflumethiazide,bumetanide, chlortalidone, cyclopenthiazide, furosemide, indapamide,metolazone, spironolactone and torasemide.39) Dopamine agonists such as, for example, amantadine, apomorphine,bromocriptine, cabergoline, lisuride, pergolide, pratnipexole andropinerole.40) Drugs for treating erectile dysfunction, such as, for example,apomorphine, apomorphine diacetate, moxisylyte, phentolamine,phosphodiesterase type 5 inhibitors, such as sildenafil, tadalafil,vardenafil and yohimbine.41) Gastrointestinal agents such as, for example, atropine, hyoscyamine,famotidine, lansoprazole, loperamide, omeprazole and rebeprazole.42) Hormones and analogues such as, for example, cortisone, epinephrine,estradiol, insulin, Ostabolin-C, parathyroid hormone and testosterone.43) Hormonal drugs such as, for example, desmopressin, lanreotide,leuprolide, octreotide, pegvisomant, protirelin, salcotonin, somatropin,tetracosactide, thyroxine and vasopressin.44) Hypoglycaemics such as, for example, sulphonylureas includingglibenclamide, gliclazide, glimepiride, glipizide and gliquidone;biguanides including metformin; thiazolidinediones includingpioglitazone, rosiglitazone, nateglinide, repaglinide and acarbose.

45) Immunoglobulins.

46) Immunomodulators such as, for example, interferon (e.g. interferonbeta-Ia and interferon beta-Ib) and glatiramer.47) Immunosupressives such as, for example, azathioprine, cyclosporin,mycophenolic acid, rapamycin, sirolimus and tacrolimus.48) Mast cell stabilizers such as, for example, cromoglycate,iodoxamide, nedocromil, ketotifen, tryptase inhibitors and pemirolast.49) Drugs for treatment of migraine headaches such as, for example,almotriptan, alperopride, amitriptyline, amoxapine, atenolol, clonidine,codeine, coproxamol, cyproheptadine, dextropropoxypene,dihydroergotamine, diltiazem, doxepin, ergotamine, eletriptan,fluoxetine, frovatriptan, isometheptene, lidocaine, lisinopril,lisuride, loxapine, methysergide, metoclopramide, metoprolol, nadolol,naratriptan, nortriptyline, oxycodone, paroxetine, pizotifen,pizotyline, prochlorperazine propanolol, propoxyphene, protriptyline,rizatriptan, sertraline, sumatriptan, timolol, tolfenamic acid,tramadol, verapamil, zolmitriptan, and nonsteroidal anti-inflammatorydrugs.50) Drugs for treatment of motion sickness such as, for example,diphenhydramine, promethazine and scopolamine.51) Mucolytic agents such as N-acetylcysteine, ambroxol, amiloride,dextrans, heparin, desulphated heparin, low molecular weight heparin andrecombinant human DNase.52) Drugs for multiple sclerosis management such as, for example,bencyclane, methylprednisolone, mitoxantrone and prednisolone.53) Muscle relaxants such as, for example, baclofen, chlorzoxazone,cyclobenzaprine, methocarbamol, orphenadrine, quinine and tizanidine.54) NMDA receptor antagonists such as, for example, mementine.55) Nonsteroidal anti-inflammatory agents such as, for example,aceclofenac, acetaminophen, alminoprofen, amfenac, amin˜prop˜loanm,ixetrine, aspirin, benoxaprofen, bromfenac, bufexamac, carprofen,celecoxib, choline, cinchophen, cinmetacin, clometacin, clopriac,diclofenac, diclofenac sodium, diflunisal, ethenzamide, etodolac,etoricoxib, fenoprofen, flurbiprofen, ibuprofen, indomethacin,indoprofen, ketoprofen, ketorolac, loxoprofen, mazipredone,meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, parecoxib, phenylbutazone, piroxicam, pirprofen, rofecoxib,salicylate, sulindac, tiaprofenic acid, tolfenamate, tolmetin andvaldecoxib.56) Nucleic-acid medicines such as, for example, oligonucleotides, decoynucleotides, antisense nucleotides and other gene-based medicinemolecules.57) Opiates and opioids such as, for example, alfentanil, allylprodine,alphaprodine, anileridine, benzylmorphine, bezitramide; buprenorphine,butorphanol, carbiphene, cipramadol, clonitazene, codeine, codeinephosphate, dextromoramide, dextropropoxyphene, diamorphine,dihydrocodeine, dihydromorphine, diphenoxylate, dipipanone, fentanyl,hydromorphone, L-alpha acetyl methadol, levorphanol, lofentanil,loperamide, meperidine, meptazinol, methadone, metopon, morphine,nalbuphine, nalorphine, oxycodone, papaveretum, pentazocine, pethidine,phenazocine, pholcodeine, remifentanil, sufentanil, tramadol, andcombinations thereof with an anti-emetic.58) Opthalmic preparations such as, for example, betaxolol andketotifen.59) Osteoporosis preparations such as, for example, alendronate,estradiol, estropitate, raloxifene and risedronate.60) Other analgesics such as, for example, apazone, benzpiperylon,benzydamine, caffeine, cannabinoids, clonixin, ethoheptazine,flupirtine, nefopam, orphenadrine, pentazocine, propacetamol andpropoxyphene.61) Other anti-inflammatory agents such as, for example, B-cellinhibitors, p38 MAP kinase inhibitors and TNF inhibitors.62) Phosphodiesterase inhibitors such as, for example, non-specificphosphodiesterase inhibitors including theophylline, theobromine, IBMX,pentoxifylline and papaverine; phosphodiesterase type 3 inhibitorsincluding bipyridines such as milrinone, amrinone and olprinone;imidazolones such as piroximone and enoximone; imidazolines such asimazodan and 5-methyl-imazodan; imidazo-quinoxalines; anddihydropyridazinones such as indolidan and LY 181 5 12(5-(6-0˜0-1,4,5,6-tetrahydro-pyridazin-3-y˜)-I,3-dihydro-indo˜-2-one);dihydroquinolinone compounds such as cilostamide, cilostazol, andvesnarinone; motapizone; phosphodiesterase type 4 inhibitors such ascilomilast, etazolate, rolipram, oglemilast, roflumilast, ONO 6126,tolafentrine and zardaverine, and including quinazolinediones such asnitraquazone and nitraquazone analogs; xanthine derivatives such asdenbufylline and arofylline; tetrahydropyrimidones such as atizoram; andoxime carbamates such as filaminast; and phosphodiesterase type 5inhibitors including sildenafil, zaprinast, vardenafil, tadalafil,dipyridamole, and the compounds described in WO 01/19802, particularly(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine,2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine,and(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N-(I,3,5-trimethyl-4-pyrazolyl)carbamoyl]-pyrimidine).63) Potassium channel modulators such as, for example, cromakalim,diazoxide, glibenclamide, levcromakalim, minoxidil, nicorandil andpinacidil.64) Prostaglandins such as, for example, alprostadil, dinoprostone,epoprostanol and misoprostol.65) Respiratory agents and agents for the treatment of respiratorydiseases including bronchodilators such as, for example, the β2-agonistsbambuterol, bitolterol, broxaterol, carmoterol, clenbuterol, fenoterol,formoterol, vilanterol, indacaterol, levalbuterol, metaproterenol,orciprenaline, picumeterol, pirbuterol, procaterol, reproterol,rimiterol, salbutamol, salmeterol, terbutaline and the like; induciblenitric oxide synthase (iNOS) inhibitors; the antimuscarinicsipratropium, ipratropium bromide, oxitropium, tiotropium, glycopyrrolateand the like; the xanthines aminophylline, theophylline and the like;adenosine receptor antagonists, cytokines such as, for example,interleukins and interferons; cytokine antagonists and chemokineantagonists including cytokine synthesis inhibitors, endothelin receptorantagonists, elastase inhibitors, integrin inhibitors, leukotrinereceptor antagonists, prostacyclin analogues, and ablukast, ephedrine,epinephrine, fenleuton, iloprost, iralukast, isoetharine, isoproterenol,montelukast, ontazolast, pranlukast, pseudoephedrine, sibenadet,tepoxalin, verlukast, zafirlukast and zileuton.66) Sedatives and hypnotics such as, for example, alprazolam,butalbital, chlordiazepoxide, diazepam, estazolam, flunitrazepam,flurazepam, lorazepam, midazolam, temazepam, triazolam, zaleplon,zolpidem, and zopiclone.67) Serotonin agonists such as, for example,1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, buspirone,m-chlorophenylpiperazine, cisapride, ergot alkaloids, gepirone,8-hydroxy-(2-N,N-dipropylamino)-tetraline, ip saperone, lysergic aciddiethylamide, 2-methyl serotonin, mezacopride, sumatriptan, tiaspirone,trazodone and zacopride.68) Serotonin antagonists such as, for example, amitryptiline,azatadine, chlorpromazine, clozapine, cyproheptadine, dexfenfluramine,R(+)-a-(2,3-dimethoxyphenyl)-I-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanold,lasetron, fenclonine, fenfluramine, granisetron, ketanserin,methysergide, metoclopramide, mianserin, ondansetron, risperidone,ritanserin, trimethobenzamide and tropisetron.69) Steroid drugs such as, for example, alcometasone, beclomethasone,beclomethasone dipropionate, betamethasone, budesonide, butixocort,ciclesonide, clobetasol, deflazacort, diflucortolone, desoxymethasone,dexamethasone, fludrocortisone, flunisolide, fluocinolone,fluometholone, fluticasone, fluticasone proprionate, hydrocortisone,methylprednisolone, mometasone, nandrolone decanoate, neom˜cin sulphate,prednisolone, rimesolone, rofleponide, triamcinolone and triamcinoloneacetonide.70) Sympathomimetic drugs such as, for example, adrenaline,dexamfetamine, dipirefin, dobutamine, dopamine, dopexamine,isoprenaline, noradrenaline, phenylephrine, pseudoephedrine, tramazolineand xylometazoline.71) Nitrates such as, for example, glyceryl trinitrate, isosorbidedinitrate and isosorbide mononitrate.72) Skin and mucous membrane agents such as, for example, bergapten,isotretinoin and methoxsalen.73) Smoking cessation aids such as, for example, bupropion, nicotine andvarenicline.74) Drugs for treatment of Tourette's syndrome such as, for example,pimozide.75) Drugs for treatment of urinary tract infections such as, forexample, darifenicin, oxybutynin, propantheline bromide and tolteridine.

76) Vaccines.

77) Drugs for treating vertigo such as, for example, betahistine andmeclizine.78) Therapeutic proteins and peptides such as acylated insulin,glucagon, glucagon-like peptides, exendins, insulin, insulin analogues,insulin aspart, insulin detemir, insulin glargine, insulin glulisine,insulin lispro, insulin zinc, isophane insulins, neutral, regular andinsoluble insulins, protamine zinc insulin, antibodies and antibodyfragments.79) Anticancer agents such as, for example, anthracyclines, doxorubicin,idarubicin, epirubicin, methotrexate, taxanes, paclitaxel, docetaxel,cisplatin, vinca alkaloids, vincris tine and 5-fluorouracil.80) Pharmaceutically acceptable salts or derivatives of any of theforegoing.

It should be noted that medicaments listed above under a particularindication or class may also find utility in other indications. Aplurality of medicaments can be employed in the practice of the presentinvention. A drug delivery system according to the invention may also beused to deliver combinations of two or more different medicaments.

In one embodiment of the invention the medicament or combination ofmedicaments are suitable for the treatment of a respiratory disorder. Inone embodiment the respiratory disorder is asthma or COPD.

In one embodiment the pharmaceutically active material is selected froma long-acting muscarinic antagonist and/or long-acting beta-adrenoceptoragonist and/or an inhaled corticosteroid.

In one embodiment the medicament is selected from budesonide, formoterolfumarate dihydrate, tiotropium, fluticasone propionate, salmeterolxinafoate, vilanterol trifenatate, umeclidinium bromide, glycopyrroniumbromide or indacaterol maleate.

In one embodiment the pharmaceutically active material is glycopyrroniumbromide. In one embodiment the pharmaceutically active material is acombination of glycopyrronium bromide and indacaterol maleate.

In one embodiment the medicament is selected from budesonide andformoterol fumarate dehydrate. In one embodiment the medicament isselected from fluticasone propionate and salmeterol xinafoate. In oneembodiment the medicament is selected from fluticasone propionate andvilanterol trifenatate. In one embodiment the medicament is selectedfrom umeclidinium bromide and vilanterol trifenatate.

Containers and Inhalation Devices

It is another aim of the present invention to provide a containercomprising conditioned taurine or a composition comprising conditionedtaurine. Containers which are suitable for use in the present inventioninclude either a bulk storage container, such as a multi-dose reservoirfor a dry powder inhaler, or unit dose containers such as a capsule or ablister. The capsule may be formed from various materials e.g. gelatine,cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) orhydroxypropylcellulose (HPC), starch, starch derivatives, chitosan orsynthetic plastics, while the blister may be provided in the form of ablister pack or blister strip.

Containers which are also considered suitable for use in the presentinvention include pMDI canisters.

Administration

In a further aspect of the present invention, the conditioned taurine ora composition comprising conditioned taurine, suitable for inhalation,are preferably administered via a dry powder inhaler (DPI). In a drypowder inhaler, the dose to be administered is stored in the form of anon-pressurized dry powder and, on actuation of the inhaler theparticles of the powder are expelled from the device in the form of acloud of finely dispersed particles that may be inhaled by the patient.

Dry powder inhalers can be “passive” devices in which the patient'sbreath is the only source of gas which provides a motive force in thedevice. Examples of “passive” dry powder inhaler devices include theRotahaler™ and Discus/Diskhaler™, the Monohaler™, the GyroHaler™Turbuhaler™ and Novolizer™. Alternatively, “active” devices may be used,in which a source of compressed gas or alternative energy source isused. Examples of suitable active devices include Aspirair™ and theactive inhaler device produced by Nektar Therapeutics (as covered byU.S. Pat. No. 6,257,233).

It is generally considered that different compositions performdifferently when dispensed using passive and active type inhalers.Passive devices create less turbulence within the device and the powderparticles are moving more slowly when they leave the device. This leadsto some of the metered dose remaining in the device and, depending onthe nature of the composition, less de-agglomeration upon actuation.However, when the slow moving cloud is inhaled, less deposition in thethroat is often observed. In contrast, active devices create moreturbulence when they are activated. This results in more of the metereddose being extracted from the blister or capsule and betterde-agglomeration as the powder is subjected to greater shear forces.However, the particles leave the device moving faster than with passivedevices and this can lead to an increase in throat deposition.

Particular “passive” dry powder inhalers that may be mentioned hereinare “passive” dry powder inhalation devices that are described in WO2010/086285. Particularly, “active” dry powder inhalers that may bementioned herein are referred to as Aspirair® inhalers and are describedin more detail in WO 2001/00262, WO 2002/07805, WO 2002/89880 and WO2002/89881. It should be appreciated, however, that conditioned taurineor a composition comprising conditioned taurine of the present inventioncan be administered with either passive or active inhaler devices.

In another aspect of the present invention, the conditioned taurine or acomposition comprising conditioned taurine, suitable for inhalation, arepreferably administered via a spray or aerosol device, such as apressurised metered dose inhaler (pMDI). The composition (whether insolution or suspension) may be for pulmonary, nasal, buccal or topicaladministration, but preferably for pulmonary inhalation.

The pMDI is dependent upon the propulsive force of a propellant systemused in its manufacture to dispense the composition from the device in aform that may be inhaled by a patient. The propellant generallycomprises a mixture of liquefied hydrofluorocarbons (HFAs) which areselected to provide the desired vapour pressure and stability of theformulation. Propellants HFA 227 (1,1,1,2,3,3,3-heptafluoropropane) andHFA 134a (1,1,1,2-tetrafluoroethane) or mixtures thereof are currentlythe most widely used propellants in aerosol formulations for inhalationadministration.

Additional embodiments of the invention include the following:

Conditioned taurine suitable for inhalation.

Conditioned taurine which is crystalline.

Conditioned taurine as an inhalation excipient.

A pharmaceutical composition comprising conditioned taurine.

A pharmaceutical composition comprising conditioned taurine furthercomprising an amino acid. The amino acid may be selected from the groupconsisting of alanine, leucine, isoleucine, lysine, valine, methionineor phenylalanine, in one embodiment leucine. The leucine may be presentin an amount less than 10%, less than 9%, less than 8%, less than 7%,less than 6%, less than 5%, less than 4%, less 3%, less than 2%, lessthan 1% by weight based on the dry weight of the composition.

A pharmaceutical composition comprising conditioned taurine furthercomprising a medicament or combinations of medicaments.

A pharmaceutical composition of the invention wherein the taurine and atleast one other component are co-spray-dried using the spray dryingconditions effective to produce conditioned taurine.

A pharmaceutical composition of the invention suitable for inhalation.

A pharmaceutical composition of the invention wherein the conditionedtaurine acts as an excipient, carrier or diluent.

A pharmaceutical composition of the invention where the amino acid islocated on the surface of the conditioned taurine.

Conditioned taurine made by a spray-drying method comprising:

-   -   (a) providing a feedstock comprising raw taurine in an aqueous        solution or suspension; and    -   (b) spray-drying the feedstock under conditions to create        particles that demonstrate no significant net change in the D₉₀        (±20%) after 7 days of ambient storage and have a particle size        (D₉₀) of <20 μm, but more preferably <10 μm after 7 days of        ambient storage.

A further embodiment of the invention is a method for preparingconditioned taurine comprising:

-   -   (a) providing a feedstock comprising raw taurine in an aqueous        solution or suspension; and    -   (b) spray-drying the feedstock under conditions to create        particles that demonstrate no significant net change in the D₉₀        (±20%) after 7 days of ambient storage and have a particle size        (D₉₀) of <20 μm, but more preferably <10 μm after 7 days of        ambient storage.

A further embodiment is a method of the invention wherein the pH of thefeedstock is between pH 1 and pH 7, in one embodiment between pH 3 andpH 5.

A further embodiment is a method of the invention wherein the pH of thefeedstock is acidic e.g. less than pH 5, in one embodiment equal to orless than pH4, such as about pH4.

A further embodiment is a method of the invention wherein the feedstockconcentration of taurine is between 0.1% and 10%, in one embodimentbetween 1% and 5%.

A further embodiment is a method of the invention wherein the feedstockconcentration of taurine is less than 5%, such as less than 4%, such asless than 3%, such as less than 2%, such as about 1%.

A further embodiment is a method of the invention wherein the feedstocktemperature is between 0.1° C. and 100° C., in one embodiment between20° C. and 70° C.

A further embodiment is a method of the invention wherein the feedstocktemperature is less than 70° C., such as less than 60° C., such as lessthan 50° C., such as less than 40° C. such as less than 30° C.

A further embodiment is a method of the invention wherein the outlettemperature of the spray drying apparatus is between 50° C. and 120° C.,in one embodiment between 60° C. and 100° C.

A further embodiment is a method of the invention wherein the outlettemperature is less than 100° C., in one embodiment less than 90° C., inone embodiment less than 80° C., still in one embodiment less than 70°C., such as about 60° C.

A further embodiment is a method of the invention wherein theT_((solid:gas)) ratio is between 2.00×10⁻⁶ and 2.75×10⁻³.

A further embodiment is a method of the invention for preparingconditioned taurine wherein the conditioned taurine particles have aparticle size (D₉₀) that remain below 20 μm after 7 days of ambientstorage post spray drying.

A further embodiment is a method of the invention used to make acomposition comprising taurine which further comprises an amino acid,e.g. selected from the group consisting of alanine, leucine, isoleucine,lysine, valine, methionine or phenylalanine, in one embodiment leucine.

A further embodiment is a method of the invention used to make acomposition comprising taurine which further comprises a medicament orcombinations of medicaments.

A further embodiment is a container comprising:

-   -   (a) conditioned taurine; or    -   (b) a composition comprising conditioned taurine

The container may be a reservoir for a dry powder inhaler, a blister ora capsule. In one embodiment the container is a blister such as a foilblister.

Conditioned taurine having a moisture content of less than 2% by weight,optionally less than 1% by weight, optionally less than 0.5% by weightof conditioned taurine.

Optionally the composition further comprises leucine and a medicament orcombinations of medicaments. The composition may be a powder.

EXAMPLES

The following examples are provided to illustrate the invention butshould not be construed as limiting the invention.

Example 1 Experimental Spray Drying Strategy Zwitterionic Hypothesis:

As taurine is a zwitterionic compound, it is believed that thesulphur-hydyl group of the taurine becomes ionised (oxidation) with theproton being added to the amine group (reduction), in the feedstock andretains a charge even after drying. This leads to the material relaxingon storage which is believed to be the charged groups neutralisingresulting in a conformatorial structural change. This conformatorialchange causes agglomeration of the particles in the dry state, leadingto a significant reduction in the aerosol performance. It is believedthe neutralisation has a vitrification intermediate phase, which is thecause of the agglomeration (See FIG. 7).

Materials:

Raw taurine was obtained from Sigma-Aldrich Chemicals (The oldbrickyard, New road, Gillingham, Dorset, SP8 4XT). Sodium Hydroxide,hydrochloric acid and citric acid were obtained from Fisher Scientific(Bishop Meadow Road, Loughborough, LE11 5RG).

Spray Drying Strategy:

The Taurine spray drying process was investigated by producing 24batches with varying process and formulation parameters (factors). Thesewere:

-   -   Drying Gas flow rate    -   Atomisation gas flow rate    -   Feedstock pumping rate    -   Outlet temperature    -   Feedstock temperature    -   Feedstock concentration    -   Feedstock pH and buffer/acid type

These process and formulation parameters (factors) examined also affectthe zwitterionic neutralisation process and the hypothesis behind themare discussed below. The values for the extremes and centre points(levels) for each of the factors were determined on well documentedphysical design limits for spray dryers.

Drying Gas Flow Rate Parameters and Rationale:

a) Definition of the Operation Range

The drying gas flow rates range were determined as being just highenough to maintain particles in the airstream during drying whileallowing a particle to have sufficient residence time in the dryingchamber to complete drying. A significant enough velocity is required tomaintain curvilinear flow through the equipment and prevent prematuredeposition of the particles in the drying chamber of transfer conduitbefore collection and classification in the cyclone. If the drying gasis too high, then the velocity of the particles will be too high to havesufficient time in the drying gas for complete evaporation of all of thewater from the feedstock to occur, resulting in high residual moisture(often >5.0% w/w). If particles have high residual moisture, then theyare liable to agglomerate strongly through capillary forces and ifpartial dissolution occurs, then solid bridging will occur. For thisinvestigation and for the VSD equipment, the lower limit is defined as12.0 Kg·Hr⁻¹ and the upper limit defined as 15.0 Kg·Hr⁻¹ and the centrepoint was defined as 13.5 Kg·Hr⁻¹.

b) Impact and Effect on the Zwitterionic Neutralisation

The drying gas is believed to affect the neutralisation process of thetaurine's sulphur-hydryl group, impacting the physical stability. Alower drying gas flow, results in a lower drying gas velocity, which inturn lowers the velocity of droplets and resultant particles. The lowervelocity causes a slower rate of evaporation and results in a longertime period for charge neutralisation, giving particles more stableform, preventing the storage agglomeration that has been observed.

Atomisation Gas Flow Rate Parameters and Rationale:

a) Definition of the Operation Range

The atomisation gas flow rate range was chosen to reflect the lowestlimit where particles of inhalation size range for a given nozzle areproduced. The upper limit defined as giving dry particles and nosignificant decrease in the D₅₀ of the resultant particles, at a givendrying gas flow rate. At higher atomisation flow rates,droplets/particles possess too high velocity and therefore low residencetime in the drying chamber, resulting in particles with high residualmoisture (often >5.0% w/w). If particles have high residual moisture,then they are liable to agglomeration. In extreme case, too highatomisation gas causes collisions between droplets before completedrying, leading to agglomerates being formed. For this investigation andfor the VSD equipment, the lower limit is defined as 12.0 L·min⁻¹ andthe upper limit defined as 18.0 L·min⁻¹, the centre point was defined as15.0 L·min⁻¹.

b) Impact and Effect on the Zwitterionic Neutralisation

The atomisation gas flow rate has been shown to have an impact on thephysical stability of spray dried taurine. One theory attributed to thismechanism is that there is a high degree of interaction of the atomisinggas, with the liquid, not just to form small and uniform droplets, butto catalyse the neutralisation of the zwitterionic charges, potentiallythrough oxidation of the sulphur-hydryl group of taurine.

Feedstock Pumping Rate Parameters and Rationale:

a) Definition of the Operation Range

The feedstock pumping rates range was chosen to reflect the lowest limitwhere the production rate of product was high enough to obtainsufficient material for analysis in a reasonable amount of time. Whilelower rates can be achieved, too low a feedrate would take anunreasonable amount of time to produce a batch and would have commerciallimitations. The upper level was defined as the feedrate at which, for agiven drying and atomisation gas flow rate, the particles produced werenot effectively dried due to oversaturation of the drying gas resultingin particles with high residual moisture (often >5.0% w/w). If particleshave high residual moisture, then they are liable to agglomeration. Forthis investigation and for the VSD equipment, the lower limit is definedas 1.5 mL·min⁻¹ and the upper limit defined as 4.5 mL·min⁻¹, the centrepoint was defined as 3.0 mL·min⁻¹.

b) Impact and Effect on the Zwitterionic Neutralisation

The feed rate controls the amount of feedstock in the drying chamber perunit time. Therefore, the feed rate has a direct effect on the dryingcapacity of the gas through altering the saturation concentration ofwater, which in turn alters the drying kinetics of the system andresultant particles. A low feed rate would have a larger drying capacitymargin for the drying gas resulting in faster drying and thuspotentially leading to less physically stable particles.

Outlet Temperature Parameters and Rationale:

a) Definition of the Operation Range

The outlet temperature range was chosen to reflect the lowesttemperature at which dry particles (often <5.0% w/w moisture) arecollected (for the centre-point values of feedstock flow rate,atomisation gas and drying gas flow rates). The upper temperature wasdefined as the boiling point of water, above which the kinetic rate ofevaporation only slightly increases. For this investigation and for theVSD equipment, the lower limit is defined as 60° C. and the upper limitdefined as 100° C., the centre point was defined as 80° C.

b) Impact and Effect on the Zwitterionic Neutralisation

The outlet temperature defines the thermal gradient across the dryingchamber and thus has a subsequent impact on the drying rate. Asdiscussed for the drying gas rationale, a longer time to evaporate thewater and form a particle results in a longer time to allow chargeneutrality and the conformatorial change to occur.

Feed Stock Temperature Parameters and Rationale:

a) Definition of the Operation Range

The feedstock temperature range was determined as being as low as roomtemperature, essentially 20° C., with the highest temperature wherevapour was being produced resulting in variable concentrations of thefeedstock being established throughout the run. With this in mind, 70°C. was chosen.

b) Impact and Effect on the Zwitterionic Neutralisation

The temperature of the feedstock during spray drying will also beinvestigated to access how the temperature affects the pKa of thesulphur-hydryl group. Theoretically, an increase in the temperaturecould increase the pKa of the sulphur-hydryl group from the currentrelatively low 1.49 (henderson-hasselbalch(1908)). This would mean thatless acidification and shorter drying times could be required to achievethe same level of physical stability at lower temperatures. In addition,adding heat to the feedstock increases the thermal energy in theatomised droplet which leads to a smaller thermal gradient and mayincrease the droplet drying kinetics to allow a particle to be driedquicker. As discussed in previous sections, it is hypothesised that theincreased drying rate leads to a shorter time for charge neutralisationand thus physical instability on storage.

Feedstock Concentration Parameters and Rationale:

a) Definition of the Operation Range

The feedstock concentration range was chosen as it will affect thedrying kinetics and resultant size/density of the produced particles. Aminimum of 1.0% w/v is often used to give an efficient production rate,while having acceptable PSD span. Above 5.0% w/v, the particle sizeincreases above the inhalation size range for most 2 fluid nozzles.Therefore, the lower concentration was defined as 1.0% w/v and the upperrange defined as 5.0% w/v. The centre point was defined as 2.5% w/v.

b) Impact and Effect on the Zwitterionic Neutralisation

The concentration of the feedstock could have several impacts on thedrying kinetics and resultant particle stability. As taurine'ssulphur-hydryl group is a strong acid, increasing the concentration oftaurine would mean a reduction in the pH. At a certain concentration,the taurine would generate sufficient protons to establish itself at itsisoelectric point. This is not so simple if one considers a dryingdroplet, which alters the concentration as water is lost. Therefore, theinitial pH might not necessarily be the optimum.

Feedstock Solution pH and Buffer/Acid Type Parameters and Rationale

The pH of the feedstock and the acid used to modify the pH is believedto affect the taurine stability via the zwitterionic theory and drivingthe molecule to the isoelectric point when in the feedstock solution.Acidifying the solution should allow the taurine to neutralise thesulphur-hydryl groups charge by reaching the molecules isoelectricpoint, which is calculated to be at pH 4.0 (See FIG. 8). The type ofacid to do this may be important too. If the acid boils at too a low aboiling point, or is an azeotrope, the conjugate base and associatedproton will be removed in the drying process before the particle isdried and charge neutralisation capability will be lost. But the acidand thus its residual conjugate base must be pharmaceutically acceptableas a salt forming agent, have a strong enough dissociation constant(pKa) to require very small effective concentrations to be effective anda high melting/boiling point to not be lost during drying prematurely.

Therefore, although the values for limits and operation space defined inthis investigation are specific to the VSD spray dryer, the experimentalstrategy can be said to cover the complete operation space for spraydrying that can be translated and transposed onto any spray dryer modelat any scale where these physical limits and constraints exist.

Batch Preparation:

24 raw taurine samples were dissolved in an appropriate amount ofMilli-Q water and sonicated. The pH of each sample was adjustedaccordingly. The prepared feedstock solutions were separatelyspray-dried using a VSD spray-drier with a 0.5 mm, two-fluid nozzleusing various combinations of the process and formulation parameterssummarised in Table 1.

Drying Outlet Feed Feedstock Feedstock Atomisation Batch Gas TemperatureRate Temperature Concentration Buffer pH Flow Rate 1 15 100 4.5 70 1Citrate 4.0 15 2 13.5 80 4.5 70 1 N/A 5.5 12 3 13.5 100 1.5 45 2.5 N/A5.5 15 4 15 100 3 20 1 N/A 5.5 12 5 12 80 3 20 1 HCl 4.0 18 6 12 100 345 5 Citrate 4.0 12 7 13.5 60 1.5 45 1 NaOH 7.0 18 8 15 60 3 70 2.5 NaOH7.0 12 9 13.5 60 4.5 20 2.5 Citrate 4.0 18 10 13.5 80 3 70 5 Citrate 4.018 11 15 100 4.5 45 5 HCl 4.0 18 12 12 60 3 45 2.5 N/A 5.5 18 13 15 80 320 5 NaOH 7.0 15 14 13.5 100 3 70 2.5 HCl 4.0 15 15 12 60 1.5 70 1 HCl4.0 12 16 15 80 4.5 45 2.5 HCl 4.0 12 17 12 60 4.5 70 5 N/A 5.5 15 18 1560 1.5 45 1 Citrate 4.0 15 19 13.5 60 1.5 20 5 HCl 4.0 15 20 12 80 1.520 2.5 Citrate 4.0 12 21 12 80 4.5 45 1 NaOH 7.0 15 22 13.5 100 4.5 20 5NaOH 7.0 12 23 15 80 1.5 70 5 N/A 5.5 18 24 12 100 1.5 70 2.5 NaOH 7.018Table 1 summaries the various combinations of the process andformulation parameters analysed

(i) Particle Size Distribution Analysis:

Particle size distributions of the 24 sample batches were measured bylaser diffraction using a Sympatec HELOS and RODOS particle sizeanalyser and ASPIROS dispersion unit (0.5 bar dispersion). A focallength corresponding to R4 lens was used and each batch sample was runin triplicate in order to determine the average particle size. In thisinstance, the D₉₀ for each batch sample was derived from the diffractiondata using in-built Sympatec software (WINDOX 5.0).

Out of the 24 sample batches analysed, only 8 sample batches (Table 2)were identified as forming conditioned taurine and demonstrated aparticle size distribution of D₉₀<10.0 μm.

TABLE 2 summarises the PSD (D₉₀) R4 lens at T=0 and T=7 days PSD R4 D₉₀PSD R4 D₉₀ Mean Sample Mean (μm) T=0 (μm) T=7days 11 7.42 8.90 13 8.308.79 15 4.82 5.80 16 8.19 8.44 17 7.89 8.17 19 7.86 7.91 20 6.51 7.34 236.62 6.89

Table 2, highlights the change in the D₉₀ using the R4 lens, frominitial (T=0) to the 7 day time point (T=7 days). All 8 samples show asmall increase (±20%) in the D₉₀ between the initial and 7 day timepoint and consequently the absence of any agglomeration.

FIG. 1, which depicts a model response plot for all 24 sample batchesproduced, similarly demonstrates that only 8 have an acceptable PSDprofile after 7 days of storage. Statistical analysis reveals that themodel was highly significant with an R²=1.00 and significant P value ofp<0.05, meaning the null hypothesis is rejected and that the parametersmodelled are significantly affecting the agglomeration potential of thetaurine. The parameters that govern the production of conditionedtaurine are feedstock concentration, feedstock pumping rate, drying gasflow rate and second/third order interactions between them.

The joint factor tests indicate from the p-values calculated (see FIG.9), that all the factors tested are significant.

Taurine can be produced in a form for inhalation that meets the particlesize criteria and particle size stability provided the spray dryingprocess is carefully controlled. The control of the parameters is usedto allow zwitterionic neutralisation during drying, to prevent thisoccurring during storage resulting in agglomeration and loss of primaryparticles. The data verifies the hypothesis that zwitterionicneutralisation is the most likely mechanism responsible foragglomeration in the solid state and that all of the process andformulation parameters tested in this investigation have an impact onthis process.

While the model and analysis are specific to the VSD, the full operationspace of the dryers capability has been mapped. Therefore, it can beinferred that inhalation taurine produced on any spray dryer and at anyscale will exhibit the same dependence on all the parameters andleverages, which control the neutralisation of the zwitterionic charge.It would be straightforward, for any person skilled in the art to mapthe operation space of a spray dryer and achieve a similar model, withthe same level of interdependence of the factors on the production ofconditioned taurine.

(ii) Calculating the Ratio of Taurine Dried Per Unit Time During SprayDrying

It has been determined that the inter-relationship between theseparameters (feedstock concentration, feedstock pumping rate and dryinggas flow rate) can be explained using the following expression, whichcalculates the amount of taurine being dried versus the amount of dryinggas present, per unit time.

$T_{{Solid}:{Gas}} = \frac{( {C_{F} \times R_{F}} )}{V_{DG}}$

Where:

T_(solid:Gas)=Mass of taurine per volume of drying gas per unit time(AU)C_(F)=Feedstock Concentration (g mL⁻¹)R_(F)=Feedrate (mL min⁻¹)V_(DD)=Volume of Drying Gas (g min⁻¹)

It has been determined by experiment that processed taurine andconditioned taurine products can be produced by spray drying when theT_((solid:gas)) ratios are between 2.000×10⁻⁶ (smallest ratio) and2.750×10⁻³ (largest ratio). The use of a more acidic feedstock is also asignificant factor (though not essential) and allows a wider operationwindow of parameters to be used in the production of conditionedtaurine.

Furthermore, to demonstrate that the calculated ratios are applicable toany open loop spray dryer, extrapolations to the Niro spray dryer areshown as exemplification:

-   -   Smallest ratio=3.529×10⁻⁶    -   Largest ratio=2.118×10⁻³

These calculated ratios fall within the range of the VSD spray dryerratios.

FIG. 2 depicts a visual variability chart showing the spread of theacceptable batches (i.e. conditioned taurine) produced as a function ofthe T_(solid:Gas) ratios and indicates the relatively even spread acrossthe theoretically operation range for the VSD spray dryer. Furthermore,the theoretical Niro spray dryer parameters are also seen to fall withinthe VSD operational range.

FIG. 3 demonstrates the strong relationship of the conditioned taurinebatches which obeys a quadratic relationship with the D₉₀ of the PSDafter 7 days. Therefore, a batch of any inhalable PSD that is stablei.e. conditioned can be made on any spray dryer at any scale using thequadratic equation defined below. Rearranging the equation will give anappropriate t-ratio which can then be used to select the appropriatedrying gas, feed rate and concentration for that dryer based on itsfunctional operation parameter ranges.

D ₉₀ (μm)=A+BX−CX ²

Where: X=T-Ratio A=6.8 B=3450.4 C=6230437.9

(iii) Thermogravimetric Analysis:

Thermogravimetric analysis (TGA) determines the changes in sample weightin relation to change in temperature. This technique is used to examinethe weight loss due to the removal of water upon heating and gives anassessment of the moisture content of the spray dried taurine samples.

TABLE 3 summarises the equipment and method used Equipment Perkin ElmerTGA 5000 Starting Temperature 25° C. End Temperature 200° C. HeatingRate 10° C./min⁻¹

FIG. 4 illustrates the moisture content for each sample at the initialtime point, T=0. All samples were below 0.2% w/w moisture.

FIG. 5 illustrates the moisture content for each sample at the 7 daytime point, T=7. All samples were below 0.2% w/w moisture, with theexception of sample batch 21 which measured 0.45% w/w moisture. In someinstances the results obtained gave a negative weight loss. This wasattributed to the balance drift in conjunction with the very smallweight loss experienced and these results were subsequently reported asa zero-weight loss.

Spray drying raw taurine, irrespective of the spray drying conditionsused, resulted in spray-dried taurine demonstrating very low moisturecontent (0.2% w/w in comparison to spray-dried trehalose, which istypically between 3% and 5% w/w). Furthermore, there was no significantchange in moisture content during storage.

(iv) Differential Scanning Calorimetry

Differential Scanning calorimetry (DSC) is a thermo-analysis techniquein which the difference in the amount of heat required to increase thetemperature of a sample and reference is measured as a function oftemperature. This technique is used to assess the glass Transitiontemperatures (Tg) and melting characteristics of the spay-dried samples.

FIG. 6 illustrates a DSC graph depicting spray-dried taurine,exemplified with sample 2 data.

A glass transition temperature was not observed for any of the samplesanalysed, indicating that, irrespective of the spray drying conditionsused, a transition from an amorphous form to crystalline does not occur,therefore the samples are produced in the crystalline form. The majorityof samples examined demonstrated a melting point at approximately 333°C., with the lowest observed melting point seen at approximately 325° C.

Example 2 Materials

Raw taurine and L-Leucine were obtained from Sigma-Aldrich Chemicals(The old brickyard, New road, Gillingham, Dorset, SP8 4XT). Trehalosewas obtained from Ferro Pfanstiehl and Salbutamol sulphate was obtainedfrom Cambrex Pharmaco.

Preparation of Salbutamol Sulphate/Taurine OR Trehalose/L-LeucineSamples:

Salbutamol sulphate (1% w/w), raw taurine OR trehalose (98.5% w/w) andL-Leucine (0.5% w/w) samples were dissolved in Milli-Q-water (800 ml)and sonicated. The prepared feedstock solutions were separatelyspray-dried using the Niro Mobile Minor X3000 with a 0.5 mm, two-fluidnozzle, according to the parameters outlined below in Table 4 and 5:

Time PSD Sample Parameters Storage Point D₁₀ D₅₀ D₉₀ Tre/Leu/ Process A0 0.73 1.65 3.44 Sal Ambient 24 h 0.82 2.27 245.71 25° C./ 24 h NA NA NA50% RH Tau/Leu/ Process B 0 0.75 1.75 3.86 Sal Ambient 24 h 0.75 1.743.80 25° C./ 24 h 0.76 1.79 4.03 50% RH Tre/Leu/ Process B 0 0.72 1.593.20 Sal Ambient 24 h 0.94 75.80  279.99 25° C./ 24 h NA NA NA 50% RHTable 4 Summarises the PSD R4 lens at T=0 and T=24

Process A is a spray drying process using appropriate spray dryingconditions specific to the Niro Mobile Minor X3000 for producing optimaltrehalose particles suitable for inhalation. It should be noted thatthese conditions can be modified by a person skilled in the art toensure that trehalose particles suitable for inhalation are producedregardless of the spray drying machine used.

Process B is a spray drying process using appropriate spray dryingconditions specific to the Niro Mobile Minor X3000 for producing optimaltaurine particles, namely conditioned taurine, suitable for inhalation.These conditions can also be modified depending on the spray dryingmachine used.

TABLE 5 summarises the spray drying parameters for Process A and ProcessB Process Conditions Used Component Parameters Process A Process BDrying Gas Pressure 30 +/− 5.0 mm Wg⁻¹ Outlet  90.0° C. +/− 3.0° C. 60.0° C. +/− 3.0° C. Temperature Inlet 160.0° C. +/− 3.0° C. 120.0° C.+/− 3.0° C. Temperature Feedstock Temperature  20.0° C. +/− 5.0° C. 50.0° C. +/− 5.0° C. Concentration 2.5% w/v Atomisation Flow Rate 150+/− 10 L min⁻¹ 200 +/− 10 L min⁻¹ Gas Pressure 1.6 +/− 0.2 bar 3.94 +/−0.2 bar

Table 4 demonstrates that storage of Tre/Leu/Sal samples, processedunder either “A” or “B” conditions and stored at 25° C./50% RH resultedin extreme agglomeration (represented by an N/A) due to an uptake ofmoisture resulting in total physical loss of primary particles e.g.agglomeration induced through amorphous crystallisation. OnlyTau/Leu/Sal samples (FIG. 16) stored at 25° C./50% RH (process B)resulted in measurable PSD values. Furthermore these values (D₁₀, D₅₀and D₉₀) were all <10 μm.

Example 3 Preparation of Glycopyrronium Bromide/Taurine/L-LeucineSamples

Glycopyrronium bromide (1.0% w/w), raw taurine (96.5% w/w) and L-leucine(2.5% w/w) samples were dissolved in Milli-Q water (60 mL) andsonicated. The prepared feedstock solution was spray dried using alaboratory spray dryer using a 0.5 mm, two fluid nozzle, 48.0 L·min⁻¹atomisation flow rate, 25.5 kg·hr⁻¹ drying gas flow rate, 60.0° C.outlet temperature and 5.0 g·min⁻¹ feed rate. Spray drying parametersidentified as appropriate for producing taurine particles suitable forinhalation.

Preparation of Glycopyrronium Bromide/Trehalose/L-Leucine Samples:

Glycopyrronium bromide (1.0% w/w), raw trehalose dihydrate (89.0% w/w inthe dried product) and L-leucine (10.0% w/w) samples were dissolved inMilli-Q water (100 mL) and sonicated. The prepared feedstock solutionwas spray dried using a laboratory spray dryer using a 0.5 mm, two fluidnozzle, 42.0 L·min⁻¹ atomisation flow rate, 18.0 kg·hr⁻¹ drying gas flowrate, 70.0° C. outlet temperature and 2.0 g·min⁻¹ feed rate. Spraydrying parameters identified as appropriate for producing taurineparticles suitable for inhalation.

Conditioning of Samples

The taurine based formulation was stored in an open jar at ambientconditions overnight to condition the samples prior to analysis.

The trehalose based formulation was stored in a sealed jar under lowhumidity (<5% RH) prior to analysis.

Each formulation was assessed for PSD, KF and assay/content at theinitial time point. For the taurine sample this corresponds to thepowder after storage in an open jar at ambient conditions overnight. Fortrehalose this corresponds to the powder after storage overnight in asealed jar under low humidity (<5% RH).

Each formulation was then assessed for PSD and drug content after 24hours storage open at a constant relative humidity (% RH) of 53% RH and23±3° C.

Particle Size Distribution (PSD)

Particle size distributions of the samples were measured by laserdiffraction using a Sympatec HELOS and RODOS particle size analyser andASPIROS dispersion unit (1.0 bar dispersion). A focal lengthcorresponding to R4 lens was used and each batch sample was run intriplicate in order to determine the average particle size. In thisinstance, the D₉₀ for each batch sample was derived from the diffractiondata using in built Sympatec software (WINDOX 5.0).

Moisture Content by Karl Fischer (KF)

Karl Fischer (KF) analysis is used to assess the water content of solidformulations using the Metrohm 774 Oven Sample Processor and 756KFCoulometer. The solid formulations were heated to a set temperature of120.0° C. and titrated using the coulometer until no water is remainingin the sample. 10 mg of each powder was weighed and the samplesassessed. This was performed on both the taurine and trehalose basedformulations.

Aerosol Performance Testing

The Fast Screening Impactor (FSI) was used to assess the aerosolisationproperties of the powder. Each formulation was assessed usinggravimetric analysis, which involved filling a blister with theformulation (12.5±1.0 mg) and firing into the FSI. The mass of thepowder evacuated from the blister and the mass collected on the finefraction collector filter paper can then be calculated to evaluate howwell the formulation is aerosolised. Water was used as the diluent forthe insert.

Drug Content Assay

The drug content of the taurine and trehalose based formulations wereassessed using High Performance Liquid Chromatography (HPLC) at theinitial time point and after 24 hours to assess the chemical stabilityof the formulations.

All data is summarised in table 6.

Drug % Mean Mean Mean Assay FPF Formulation/ D10 D50 D90 (% <5 μm KFCondition Time point (μm) (μm) (μm) Nominal) t = 0 (% w/w) Trehalose/Initial 0.73 1.65 3.43 103.1 70.2 2.59 glycopyrronium 24 hours at Noresult - solid 91.2 bromide 53% RH compact formed, 27 days at mechanicalforce ambient required to break up compact Taurine/ Initial 0.76 1.794.02 100.7 40.3 0.41 glycopyrronium 24 hours at 0.77 1.87 4.27 98.6bromide 53% RH 27 days at 0.77 1.85 4.23 ambientTable 6 Summarises the data for glycopyrronium bromide T=0, 24 hours and27 days

Table 6 demonstrates that both taurine and trehalose based formulationsare aerosolisable and respirable at the initial time point.

After 24 hours storage at 53% RH the trehalose formulation hasagglomerated and is no longer respirable, a PSD assessment was not ableto be performed due to the formation of a solid compact. Additionally,the drug content dropped from 103% of nominal to 91% of nominal,indicating this is not chemically stable. Whereas, after 24 hoursstorage at 53% RH the taurine formulation has remained respirable(D₉₀<10 μm), and is chemically stable. After 27 days storage at ambientconditions the taurine particles remain respirable and aerosolisable.

Example 4 Preparation of Salbutamol Sulphate/Taurine/L-Leucine Samples

Salbutamol sulphate (1.0% w/w), raw taurine (96.5% w/w) and L-leucine(2.5% w/w) samples were dissolved in Milli-Q water (60 mL) andsonicated. The prepared feedstock solution was spray dried using a spraydryer using a 0.5 mm, two fluid nozzle, 48.0 L·min⁻¹ atomisation flowrate, 25.5 kg·hr⁻¹ drying gas flow rate, 60.0° C. outlet temperature and5.0 g·min⁻¹ feed rate. Spray drying parameters identified as appropriatefor producing taurine particles suitable for inhalation.

The taurine based formulation was stored in an open jar at ambientconditions overnight to condition the samples.

The formulation was assessed for PSD, KF and assay/content at theinitial time point.

The formulation was then assessed for PSD and drug content after 24hours storage open at a constant relative humidity (% RH) of 53% RH and23±3° C.

Particle Size Distribution (PSD)

Particle size distributions of the samples were measured by laserdiffraction using a Sympatec HELOS and RODOS particle size analyser andASPIROS dispersion unit (1.0 bar dispersion). A focal lengthcorresponding to R4 lens was used and each batch sample was run intriplicate in order to determine the average particle size. In thisinstance, the D₉₀ for each batch sample was derived from the diffractiondata using in built Sympatec software (WINDOX 5.0).

Moisture Content by Karl Fischer (KF)

Karl Fischer (KF) analysis is used to assess the water content of solidformulations using the Metrohm 774 Oven Sample Processor and 756KFCoulometer. The solid formulations were heated to a set temperature of120.0° C. and titrated using the coulometer until no water is remainingin the sample. 10 mg of each powder was weighed and the samplesassessed.

Aerosol Performance Testing

The Fast Screening Impactor (FSI) was used to assess the aerosolisationproperties of the powder. Each formulation was assessed usinggravimetric analysis, which involved filling a blister with theformulation (12.5±1.0 mg) and firing into the FSI. The mass of thepowder evacuated from the blister and the mass collected on the finefraction collector filter paper can then be calculated to evaluate howwell the formulation is aerosolised. Water was used as the diluent forthe insert.

Drug Content Assay

The drug content of the taurine based formulation was assessed usingHigh Performance Liquid Chromatography (HPLC) at the initial time pointand after 24 hours to assess the chemical stability of the formulation.

All data is summarised in Table 7.

Drug % For- Mean Mean Mean Assay FPF KF mulation/ Time D10 D50 D90 (% <5μm (% Condition point (μm) (μm) (μm) Nominal) t = 0 w/w) Taurine,Initial 0.77 1.87 4.26 97.9 42.0 0.5 Salbu- 24 hours 0.78 1.92 4.38 99.4tamol at sulphate 53% RH 26 days at 0.78 1.92 4.38 ambientTable 7 Summarises the data for salbutamol sulphate T=0 and T=24 hours

Table 7 demonstrates that the taurine based formulation is aerosolisableand respirable at the initial time point. After 24 hours storage at 53%RH the taurine formulation remains respirable (D₉₀<10 μm) and chemicallystable. After 26 days at storage at ambient conditions the taurineformulation remains respirable and aerosolisable.

Example 5 Preparation of Sumatriptan Succinate/Taurine/L-Leucine Samples

Sumatriptan succinate (1.0% w/w), raw taurine (96.5% w/w) and L-leucine(2.5% w/w) samples were dissolved in Milli-Q water (60 mL) andsonicated. The prepared feedstock solution was spray dried using a spraydryer using a 0.5 mm, two fluid nozzle, 48.0 L·min⁻¹ atomisation flowrate, 25.5 kg·hr⁻¹ drying gas flow rate, 60.0° C. outlet temperature and5.0 g·min⁻¹ feed rate. Spray drying parameters identified as appropriatefor producing taurine particles suitable for inhalation.

The taurine based formulation was stored in an open jar at ambientconditions overnight to condition the samples.

The formulation was assessed for PSD, KF and assay/content at theinitial time point.

The formulation was then assessed for PSD and drug content after 24hours storage open at a constant relative humidity (% RH) of 53% RH and23±3° C.

Particle Size Distribution (PSD)

Particle size distributions of the samples were measured by laserdiffraction using a Sympatec HELOS and RODOS particle size analyser andASPIROS dispersion unit (1.0 bar dispersion). A focal lengthcorresponding to R4 lens was used and each batch sample was run intriplicate in order to determine the average particle size. In thisinstance, the D₉₀ for each batch sample was derived from the diffractiondata using in built Sympatec software (WINDOX 5.0).

Moisture Content by Karl Fischer (KF)

Karl Fischer (KF) analysis is used to assess the water content of solidformulations using the Metrohm 774 Oven Sample Processor and 756KFCoulometer. The solid formulations were heated to a set temperature of120.0° C. and titrated using the coulometer until no water is remainingin the sample. 10 mg of each powder was weighed and the samplesassessed.

Aerosol Performance Testing

The Fast Screening Impactor (FSI) was used to assess the aerosolisationproperties of the powder. Each formulation was assessed usinggravimetric analysis, which involved filling a blister with theformulation (12.5±1.0 mg) and firing into the FSI. The mass of thepowder evacuated from the blister and the mass collected on the finefraction collector filter paper can then be calculated to evaluate howwell the formulation is aerosolised. Water was used as the diluent forthe insert.

Drug Content Assay

The drug content of the taurine based formulations was assessed usingultraviolet (U.V.)

analysis at the initial time point and after 24 hours to assess thechemical stability of the formulation.

% For- Mean Mean Mean Drug FPF mulation/ Time D10 D50 D90 Assay (% <5 μmCondition point (μm) (μm) (μm) Nominal) t = 0 KF Taurine, Initial 0.771.89 4.31 97.0 53.9 0.48 Suma- 24 hours 0.78 1.94 4.43 93.8 triptan atsuccinate 53% RH 26 days at 0.78 1.92 4.39 ambientTable 8 Summarises the data for sumatriptan succinate T=0 and T=24 hours

Table 8 demonstrates that the taurine based formulation is aerosolisableand respirable at the initial time point, with sumatriptan succinatepresent. After 24 hours storage at 53% RH the taurine formulationremains aerosolisable and respirable (D₉₀<10 μm) and chemically intact.After 26 days at storage at ambient conditions the taurine formulationremains respirable and aerosolisable.

Dose Ranging Study Preparation of Salbutamol Sulphate/Taurine/L-LeucineSamples:

Salbutamol sulphate, raw taurine and L-leucine samples were dissolved inthe ratios detailed in Milli-Q water (60 mL) and sonicated. The preparedfeedstock solution was spray dried using a spray dryer using a 0.5 mm,two fluid nozzle, 48.0 L·min⁻¹ atomisation flow rate, 25.5 kg·hr⁻¹drying gas flow rate, 60.0° C. outlet temperature and 5.0 g·min⁻¹ feedrate. Spray drying parameters identified as appropriate for producingtaurine particles suitable for inhalation.

The taurine based formulation was stored in an open jar at ambientconditions overnight to condition the samples.

The formulations were assessed for PSD, KF and assay/content at theinitial time point.

The formulations was then assessed for PSD and drug content after 24hours storage open at a constant relative humidity (% RH) of 53% RH and23±3° C.

TABLE 9 Formulation composition and data for salbutamol sulphate at arange of compositions T = 0 and T = 24 hours Drug Mean Mean AssayFormulation/ D10 D50 Mean % FPF (% Condition Time point (μm) (μm) D90(μm) <5 μm Nominal) KF Taurine Initial 0.77 1.87 4.26 42.0 97.9 0.596.5% w/w, 24 hours 0.78 1.92 4.38 99.4 leucine At 2.5% w/w, drug 53% RH1.0% w/w Taurine Initial 0.88 2.55 5.92 35.1 96.8 1.45 87.5% w/w, 60hours 0.96 2.93 6.52 97.8 Leucine At 2.5% w/w, drug 53% RH 10.0% w/wTaurine Initial 1.02 3.21 6.93 39 97.7 1.27 79.95% w/w, 24 hours 1.013.23 12.06 97.2 Leucine At 2.5% w/w, drug 53% RH 17.55% w/w TaurineInitial 1.26 3.87 7.75 33 97.0 0.15 77.0% w/w, 24 hours 2.38 5.4 94.5999.6 Leucine At 2.5% w/w, drug 53% RH 20.5% w/w Taurine Initial 3.157.06 80.64 25 95.3 73.1% w/w, 24 hours 2.8 6.74 86.62 95.9 Leucine At2.5% w/w, drug 53% RH 24.4% w/w

Table 9 shows that as the taurine concentration in the formulationdecreases and the drug concentration increases the physicallystabilising influence of taurine begins to diminish.

There is no agglomeration of the powder when left at ambient overnightand at 53% RH (21±3° C.) for 24 hours at taurine concentrations of 96.5%w/w and 87.5% w/w. A small amount of agglomeration is observed (n=1 rep)at 79.95% w/w taurine concentration. A larger amount of agglomeration isobserved at taurine concentrations above 77.0% w/w.

Example 6 pMDI Preparation of Salbutamol Sulphate/Taurine/L-LeucineSamples:

Salbutamol sulphate, raw taurine and L-leucine samples were dissolved inthe ratios detailed in Table 10. Milli-Q water (60 mL) and sonicated.The prepared feedstock solution was spray dried using a spray dryerusing a 0.5 mm, two fluid nozzle, 48.0 L·min⁻¹ atomisation flow rate,25.5 kg·hr⁻¹ drying gas flow rate, 60.0° C. outlet temperature and 5.0g·min⁻¹ feed rate. Spray drying parameters identified as appropriate forproducing taurine particles suitable for inhalation.

The taurine based formulation was stored in an open jar at ambientconditions overnight to condition the samples.

Preparation of Salbutamol/Taurine/L-Leucine Metered Dose Inhalers:

Formulations as listed in table 10 were weighed into 19 mL Presspartaluminium canisters. A Bespak 357 50 μL valve was crimped onto thecannister. P134a propellant was subsequently filled through the valveusing a Pamasol pressure fill system. The filled can was placed into aBespak Actuator with nominal orifice size of 0.42 mm.

Emitted Dose

Prior to testing the MDI canister was placed in a Branson 8510 modelsonic bath for five minutes. Dose Uniformity Sampling Apparatus (DUSA)with a testing flow rate of 28.3 L·min⁻¹ was used to assess the emitteddose from the MDI. Ten actuations from the MDI were fired intoindividual DUSA. The DUSA tubes were rinsed with fixed volumes ofdiluent to recover the salbutamol sulphate. Samples were analysed usingHigh Performance Liquid Chromatography (HPLC). The mean emitted dose wascalculated as the average recovery from ten DUSA.

Particle Size Distribution of Emitted Dose

Prior to testing the MDI canister was placed in a Branson 8510 modelsonic bath for five minutes. The Next Generation Impactor (NGI) with atesting flow rate of 30 L·min⁻¹ was used to assess the particle sizedistribution of the emitted dose from the MDI. Two actuations from theMDI were fired into the NGI. The MDI actuator, NGI throat and stageswere washed with fixed volumes of diluent to recover the salbutamolsulphate. Samples were analysed using High Performance LiquidChromatography (HPLC). The Impactor Sized Mass (ISM, the sum of therecovered dose on stages 2 to the micro orifice collector of the NGI)was calculated as a function of the emitted dose (i.e. the ratio betweenthe ISM and the sum of the ISM, throat and stage 1 deposition expressedas a percentage). The Mass Median Aerodynamic Diameter was determined.

Drug Content Assay

The drug content of the salbutamol sulphate in propellant in the MDIcanister was determined. Canisters were submersed in liquid nitrogen tofreeze propellant. An incision made in the valve shoulder allowed thepropellant to sublime as the MDI equilibrated to room temperature. Thecanister and valve were rinsed with fixed volumes of diluent to recoverthe salbutamol sulphate. Samples were analysed using High PerformanceLiquid Chromatography (HPLC).

Particle Size Distribution (PSD)—Prior to Use in MDI Preparation

Approximately 10 mg of formulation was dispersed in 0.2% lecithin iniso-octane and sonicated for 3 minutes using a sonic probe. The samplewas left to rest for 5 minutes then analysed for particle sizedistribution using the Malvern Mastersizer 2000, with a pump speed of3000 rpm and an obscuration of 5-10%. 6 measurements were taken for eachsample and the mean D₁₀, D₅₀ and D90 determined using the built inMalvern software.

Particle Size Distribution (PSD)—after Use in MDI Preparation

Prior to testing the MDI canister was placed in a Branson 8510 modelsonic bath for five minutes. Canisters were submersed in liquid nitrogento freeze propellant. An incision made in the valve shoulder allowed thepropellant to sublime as the MDI equilibrated to room temperature.Formulation was manually recovered from the canister. Approximately 10mg of formulation was dispersed in 0.2% lecithin in iso-octane andsonicated for 3 minutes using a sonic probe. The sample was left to restfor 5 minutes then analysed for particle size distribution using theMalvern Mastersizer 2000, with a pump speed of 3000 rpm and anobscuration of 5-10%. 6 measurements were taken for each sample and themean D10, D50 and D90 determined using the built in Malvern software.

Visual Inspection of MDI Suspensions

Formulations as listed in table 11 were weighed into plastic coatedclear glass canisters. A continuous flow valve was crimped onto thecanister. P134a propellant was subsequently filled through the valveusing a Pamasol pressure fill system. Prior to testing the MDI canisterwas placed in a Branson 8510 model sonic bath for five minutes. Eachcanister was shaken for ten seconds and placed in front of a blackbackground. Photographs were taken at 5 second intervals. Visualcomparison of the photographs versus a clear glass canister alloweddetermination of the time where the majority of the formulation was nolonger in suspension. No creaming was visible for any of thesuspensions.

TABLE 10 Formulation composition for salbutamol sulphate in a range ofMDI compositions Formulation Formulation/ per canister HFA 134a perCondition (mg) canister (mg) Taurine 87.5% w/w, Leucine 2.5% w/w, 12014700 Salbutamol Sulphate 10.0% w/w Taurine 73.1% w/w, Leucine 2.5% w/w,48 14700 Salbutamol Sulphate 24.4% w/w Taurine 120 14700 90% w/w,Salbutamol Sulphate 10.0% w/w Taurine 100% w/w 48 14700

TABLE 11 Formulation composition for salbutamol sulphate in a range ofMDI composition Formulation Formulation/ per canister HFA 134a perCondition (mg) canister (mg) Taurine 87.5% w/w, Leucine 2.5% w/w, 607350 Salbutamol Sulphate 10.0% w/w Taurine 73.1% w/w, Leucine 2.5% w/w,24 7350 Salbutamol Sulphate 24.4% w/w Taurine 60 7350 90% w/w,Salbutamol Sulphate 10.0% w/w Taurine 100% w/w 24 7350

TABLE 12 Formulation composition for salbutamol sulphate in a range ofMDI compositions Emitted Impactor Mean Mean Mean Mean Mean Mean DoseSized Drug D10 D50 D90 D10 D50 D90 Mean Visible Mass (% AssayFormulation/ Pre MDI Pre MDI Pre MDI Ex MDI Ex MDI Ex MDI (μg)Suspension of Emitted MMAD (% Condition (μm) (μm) (μm) (μm) (μm) (μm)(RSD, %) Duration (s) Dose) (μm) Nominal) Taurine 87.5% w/w, 1.0 2.9 6.51.0 2.9 6.6 50.0 15 33.9 7.10 102 Leucine 2.5% w/w, (32.2) SalbutamolSulphate 10.0% w/w Taurine 73.1% w/w, 1.2 5.8 36.0 1.1 5.7 15.081.3 >120 13.5 Not 102 Leucine 2.5% w/w, (13.0) Determined SalbutamolSulphate 24.4% w/w Taurine 1.0 3.5 7.4 1.0 3.8 7.8 46.3 20 33.8 7.39 10090% w/w, (12.0) Salbutamol Sulphate 10.0% w/w Taurine 100% w/w 1.1 2.95.9 1.1 2.8 5.5 15

1. A method for preparing conditioned taurine, the method comprising aconditioning step, wherein the conditioning step is a spray drying step,to produce taurine that: (a) demonstrates no significant net change inthe D₉₀ (±20%) after 7 days of ambient storage and (b) have a particlesize D₉₀ of <20 μm, but more preferably <10 μm after 7 days of ambientstorage;
 2. Conditioned taurine obtained by the method of claim
 1. 3.The conditioned taurine according to claim 2, which is suitable forinhalation.
 4. The conditioned taurine according to claim 2, which is atleast 95% crystalline.
 5. A composition comprising conditioned taurine,in a dry powder form suitable for inhalation, wherein the dry powderform is prepared by spray drying.
 6. A composition according to claim 5,further comprising an amino acid.
 7. A composition according to claim 5or 6, wherein the amino acid is selected from the group consisting ofalanine, leucine, isoleucine, lysine, valine, methionine orphenylalanine.
 8. A composition according to claim 5 or 6, wherein theamino acid is leucine.
 9. A composition according to claim 8, whereinthe leucine is present in an amount less than 10% by weight based on thedry weight of the composition.
 10. A composition according to claim 5,further comprising a medicament.
 11. A composition according to claim 10in which the medicament is selected from budesonide, formoterol fumaratedihydrate, tiotropium, fluticasone propionate, salmeterol xinafoate,vilanterol trifenatate, umeclidinium bromide, glycopyrronium bromide orindacaterol maleate.
 12. A composition according to claim 5, furthercomprising combinations of medicaments.
 13. A composition according toclaim 12 in which the combination of medicaments is selected frombudesonide and formoterol fumarate dehydrate; fluticasone propionate andsalmeterol xinafoate; fluticasone propionate and vilanterol trifenatate;and umeclidinium bromide and vilanterol trifenatate.
 14. (canceled) 15.A method for preparing conditioned taurine, the method comprising dryingsolubilised taurine, by spray drying with one or more of the followingparameters: (a) the pH of the feedstock to be spray dried is acidic e.g.less than pH 5, preferably equal to or less then pH 4, such as about pH4; (b) wherein the feedstock concentration is between 0.1% and 10%, morepreferably between 1% and 5%; (c) the feedstock temperature is between0.1° C. and 100° C., more preferably between 20° C. and 70° C.; (d) theoutlet temperature is between 50° C. and 120° C., more preferablybetween 60° C. and 100° C.; (e) the T_((solid:gas)) ratio is between2.00×10⁻⁶ and 2.75×10⁻³.
 16. A method for preparing conditioned taurine,the method comprising drying solubilised taurine, by spray drying withone or more of the following parameters: (a) the pH of the feedstock tobe spray dried is less then pH 4; (b) wherein the feedstockconcentration is between 1% and 5%; (c) the feedstock temperature isbetween 20° C. and 70° C.; (d) the outlet temperature is between 60° C.and 100° C.; (e) the T_((solid:gas)) ratio is between 2.00×10⁻⁶ and2.75×10⁻³.
 17. A kit comprising a container which holds one selectedfrom the group consisting of: (a) conditioned taurine; and (b) acomposition comprising conditioned taurine which is prepared by spraydrying.
 18. A container according to claim 17 selected from the groupconsisting of the reservoir for a dry powder inhaler, a blister and acapsule.
 19. A method for preparing conditioned taurine, the methodcomprising a one-step spray drying process.